Cancers

22 pages, 7030 KiB

Open AccessArticle

Anticancer Activities of 9-chloro-6-(piperazin-1-yl)-11H-indeno[1,2-c] quinolin-11-one (SJ10) in Glioblastoma Multiforme (GBM) Chemoradioresistant Cell Cycle-Related Oncogenic Signatures

by Ntlotlang Mokgautsi, Yu-Cheng Kuo, Sung-Ling Tang, Feng-Cheng Liu, Shiang-Jiun Chen, Alexander T. H. Wu and Hsu-Shan Huang

Cancers 2022, 14(1), 262; https://doi.org/10.3390/cancers14010262 - 05 Jan 2022

Cited by 4 | Viewed by 3674

Abstract

Current anticancer treatments are inefficient against glioblastoma multiforme (GBM), which remains one of the most aggressive and lethal cancers. Evidence has shown the presence of glioblastoma stem cells (GSCs), which are chemoradioresistant and associated with high invasive capabilities in normal brain tissues. Moreover, [...] Read more.

Current anticancer treatments are inefficient against glioblastoma multiforme (GBM), which remains one of the most aggressive and lethal cancers. Evidence has shown the presence of glioblastoma stem cells (GSCs), which are chemoradioresistant and associated with high invasive capabilities in normal brain tissues. Moreover, accumulating studies have indicated that radiotherapy contributes to abnormalities in cell cycle checkpoints, including the G₁/S and S phases, which may potentially lead to resistance to radiation. Through computational simulations using bioinformatics, we identified several GBM oncogenes that are involved in regulating the cell cycle. Cyclin B1 (CCNB1) is one of the cell cycle-related genes that was found to be upregulated in GBM. Overexpression of CCNB1 was demonstrated to be associated with higher grades, proliferation, and metastasis of GBM. Additionally, increased expression levels of CCNB1 were reported to regulate activation of mitogen-activated protein kinase 7 (MAPK7) in the G₂/M phase, which consequently modulates mitosis; additionally, in clinical settings, MAPK7 was demonstrated to promote resistance to temozolomide (TMZ) and poor patient survival. Therefore, MAPK7 is a potential novel drug target due to its dysregulation and association with TMZ resistance in GBM. Herein, we identified MAPK7/extracellular regulated kinase 5 (ERK5) genes as being overexpressed in GBM tumors compared to normal tissues. Moreover, our analysis revealed increased levels of the cell division control protein homolog (CDC42), a protein which is also involved in regulating the cell cycle through the G₁ phase in GBM tissues. This therefore suggests crosstalk among CCNB1/CDC42/MAPK7/cluster of differentiation 44 (CD44) oncogenic signatures in GBM through the cell cycle. We further evaluated a newly synthesized small molecule, SJ10, as a potential target agent of the CCNB1/CDC42/MAPK7/CD44 genes through target prediction tools and found that SJ10 was indeed a target compound for the above-mentioned genes; in addition, it displayed inhibitory activities against these oncogenes as observed from molecular docking analysis. Full article

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12 pages, 1510 KiB

Open AccessArticle

Association between CT-Based Preoperative Sarcopenia and Outcomes in Patients That Underwent Liver Resections

by David Martin, Yaël Maeder, Kosuke Kobayashi, Michael Schneider, Joachim Koerfer, Emmanuel Melloul, Nermin Halkic, Martin Hübner, Nicolas Demartines, Fabio Becce and Emilie Uldry

Cancers 2022, 14(1), 261; https://doi.org/10.3390/cancers14010261 - 05 Jan 2022

Cited by 11 | Viewed by 3384

Abstract

This retrospective observational study aimed to evaluate whether preoperative sarcopenia, assessed by CT imaging, was associated with postoperative clinical outcomes and overall survival in patients that underwent liver resections. Patients operated on between January 2014 and February 2020 were included. The skeletal muscle [...] Read more.

This retrospective observational study aimed to evaluate whether preoperative sarcopenia, assessed by CT imaging, was associated with postoperative clinical outcomes and overall survival in patients that underwent liver resections. Patients operated on between January 2014 and February 2020 were included. The skeletal muscle index (SMI) was measured at the level of the third lumbar vertebra on preoperative CT scans. Preoperative sarcopenia was defined based on pre-established SMI cut-off values. The outcomes were postoperative morbidity, length of hospital stay (LOS), and overall survival. Among 355 patients, 212 (59.7%) had preoperative sarcopenia. Patients with sarcopenia were significantly older (63.5 years) and had significantly lower BMIs (23.9 kg/m²) than patients without sarcopenia (59.3 years, p < 0.01, and 27.7 kg/m², p < 0.01, respectively). There was no difference in LOS (8 vs. 8 days, p = 0.75), and the major complication rates were comparable between the two groups (11.2% vs. 11.3%, p = 1.00). The median overall survival times were comparable between patients with sarcopenia and those without sarcopenia (15 vs. 16 months, p = 0.87). Based on CT assessment alone, preoperative sarcopenia appeared to have no impact on postoperative clinical outcomes or overall survival in patients that underwent liver resections. Future efforts should also consider muscle strength and physical performance, in addition to imaging, for preoperative risk stratification. Full article

(This article belongs to the Special Issue Physical Activity and Cancer Care)

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26 pages, 1734 KiB

Open AccessEditor’s ChoiceReview

Harnessing Antitumor CD4⁺ T Cells for Cancer Immunotherapy

by Myriam Ben Khelil, Yann Godet, Syrine Abdeljaoued, Christophe Borg, Olivier Adotévi and Romain Loyon

Cancers 2022, 14(1), 260; https://doi.org/10.3390/cancers14010260 - 05 Jan 2022

Cited by 25 | Viewed by 6228

Abstract

Over the past decades, CD4⁺ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4⁺ T cells during antitumor immunity. CD4⁺ T cells can [...] Read more.

Over the past decades, CD4⁺ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4⁺ T cells during antitumor immunity. CD4⁺ T cells can either suppress or promote the antitumor cytotoxic CD8⁺ T cell responses, either in secondary lymphoid organs or in the tumor. In this review, we provide an overview of the multifaceted role of different CD4⁺ T cell subsets in cancer immune response and their contribution during cancer therapies. Specifically, we focus on the latest progress regarding the impact of CD4⁺ T cell modulation on immunotherapies and other cancer therapies and discuss the prospect for harnessing CD4⁺ T cells to control tumor progression and prevent recurrence in patients. Full article

(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)

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17 pages, 6216 KiB

Open AccessArticle

Lysyl-Oxidase Dependent Extracellular Matrix Stiffness in Hodgkin Lymphomas: Mechanical and Topographical Evidence

by Massimo Alfano, Irene Locatelli, Cristina D’Arrigo, Marco Mora, Giovanni Vozzi, Aurora De Acutis, Roberta Pece, Sara Tavella, Delfina Costa, Alessandro Poggi and Maria Raffaella Zocchi

Cancers 2022, 14(1), 259; https://doi.org/10.3390/cancers14010259 - 05 Jan 2022

Cited by 4 | Viewed by 2550

Abstract

Purpose: The biochemical composition and architecture of the extracellular matrix (ECM) is known to condition development and invasiveness of neoplasms. To clarify this point, we analyzed ECM stiffness, collagen cross-linking and anisotropy in lymph nodes (LN) of Hodgkin lymphomas (HL), follicular lymphomas (FL) [...] Read more.

Purpose: The biochemical composition and architecture of the extracellular matrix (ECM) is known to condition development and invasiveness of neoplasms. To clarify this point, we analyzed ECM stiffness, collagen cross-linking and anisotropy in lymph nodes (LN) of Hodgkin lymphomas (HL), follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL), compared with non-neoplastic LN (LDN). Methods and Results: We found increased elastic (Young’s) modulus in HL and advanced FL (grade 3A) over LDN, FL grade 1–2 and DLBCL. Digital imaging evidenced larger stromal areas in HL, where increased collagen cross-linking was found; in turn, architectural modifications were documented in FL3A by scanning electron microscopy and enhanced anisotropy by polarized light microscopy. Interestingly, HL expressed high levels of lysyl oxidase (LOX), an enzyme responsible for collagen cross-linking. Using gelatin scaffolds fabricated with a low elastic modulus, comparable to that of non-neoplastic tissues, we demonstrated that HL LN-derived mesenchymal stromal cells and HL cells increased the Young’s modulus of the extracellular microenvironment through the expression of LOX. Indeed, LOX inhibition by β-aminopropionitrile prevented the gelatin stiffness increase. Conclusions: These data indicate that different mechanical, topographical and/or architectural modifications of ECM are detectable in human lymphomas and are related to their histotype and grading. Full article

(This article belongs to the Special Issue Study on Tumor Microenvironment in Lymphoma)

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23 pages, 1853 KiB

Open AccessReview

Neuropsychiatric Disorders and Frailty in Older Adults over the Spectrum of Cancer: A Narrative Review

by Mariya Muzyka, Luca Tagliafico, Gianluca Serafini, Ilaria Baiardini, Fulvio Braido, Alessio Nencioni and Fiammetta Monacelli

Cancers 2022, 14(1), 258; https://doi.org/10.3390/cancers14010258 - 05 Jan 2022

Cited by 1 | Viewed by 3278

Abstract

Background: The interplay between different neuropsychiatric conditions, beyond dementia, in the presence of a diagnosis of cancer in older adults may mediate patients’ fitness and cancer-related outcomes. Here, we aimed to investigate the presence of depression, sleep disturbances, anxiety, attitude, motivation, and support [...] Read more.

Background: The interplay between different neuropsychiatric conditions, beyond dementia, in the presence of a diagnosis of cancer in older adults may mediate patients’ fitness and cancer-related outcomes. Here, we aimed to investigate the presence of depression, sleep disturbances, anxiety, attitude, motivation, and support in older adults receiving a diagnosis of cancer and the dimension of frailty in order to understand the magnitude of the problem. Methods: This review provides an update of the state of the art based on references from searches of PubMed between 2000 and June 2021. Results: The evidence obtained underscored the tight association between frailty and unfavorable clinical outcomes in older adults with cancer. Given the intrinsic correlation of neuropsychiatric disorders with frailty in the realm of cancer survivorship, the evidence showed they might have a correlation with unfavorable clinical outcomes, late-life geriatric syndromes and higher degree of frailty. Conclusions: The identification of common vulnerabilities among neuropsychiatric disorders, frailty, and cancer may hold promise to unmask similar shared pathways, potentially intercepting targeted new interventions over the spectrum of cancer with the delivery of better pathways of care for older adults with cancer. Full article

(This article belongs to the Special Issue Neurodegeneration and Cancers)

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14 pages, 3373 KiB

Open AccessArticle

Blood-Derived Extracellular Vesicle-Associated miR-3182 Detects Non-Small Cell Lung Cancer Patients

by Kekoolani S. Visan, Richard J. Lobb, Shu Wen Wen, Justin Bedo, Luize G. Lima, Sophie Krumeich, Carlos Palma, Kaltin Ferguson, Ben Green, Colleen Niland, Nicole Cloonan, Peter T. Simpson, Amy E. McCart Reed, Sarah J. Everitt, Michael P. MacManus, Gunter Hartel, Carlos Salomon, Sunil R. Lakhani, David Fielding and Andreas Möller

Cancers 2022, 14(1), 257; https://doi.org/10.3390/cancers14010257 - 05 Jan 2022

Cited by 9 | Viewed by 3330

Abstract

With five-year survival rates as low as 3%, lung cancer is the most common cause of cancer-related mortality worldwide. The severity of the disease at presentation is accredited to the lack of early detection capacities, resulting in the reliance on low-throughput diagnostic measures, [...] Read more.

With five-year survival rates as low as 3%, lung cancer is the most common cause of cancer-related mortality worldwide. The severity of the disease at presentation is accredited to the lack of early detection capacities, resulting in the reliance on low-throughput diagnostic measures, such as tissue biopsy and imaging. Interest in the development and use of liquid biopsies has risen, due to non-invasive sample collection, and the depth of information it can provide on a disease. Small extracellular vesicles (sEVs) as viable liquid biopsies are of particular interest due to their potential as cancer biomarkers. To validate the use of sEVs as cancer biomarkers, we characterised cancer sEVs using miRNA sequencing analysis. We found that miRNA-3182 was highly enriched in sEVs derived from the blood of patients with invasive breast carcinoma and NSCLC. The enrichment of sEV miR-3182 was confirmed in oncogenic, transformed lung cells in comparison to isogenic, untransformed lung cells. Most importantly, miR-3182 can successfully distinguish early-stage NSCLC patients from those with benign lung conditions. Therefore, miR-3182 provides potential to be used for the detection of NSCLC in blood samples, which could result in earlier therapy and thus improved outcomes and survival for patients. Full article

(This article belongs to the Special Issue Liquid Nucleic Acid-Based Biomarkers in Solid Tumors)

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19 pages, 3110 KiB

Open AccessArticle

Comparative Gene Expression Analysis Reveals Similarities and Differences of Chronic Myeloid Leukemia Phases

by Annemarie Schwarz, Ingo Roeder and Michael Seifert

Cancers 2022, 14(1), 256; https://doi.org/10.3390/cancers14010256 - 05 Jan 2022

Cited by 5 | Viewed by 3300

Abstract

Chronic myeloid leukemia (CML) is a slowly progressing blood cancer that primarily affects elderly people. Without successful treatment, CML progressively develops from the chronic phase through the accelerated phase to the blast crisis, and ultimately to death. Nowadays, the availability of targeted tyrosine [...] Read more.

Chronic myeloid leukemia (CML) is a slowly progressing blood cancer that primarily affects elderly people. Without successful treatment, CML progressively develops from the chronic phase through the accelerated phase to the blast crisis, and ultimately to death. Nowadays, the availability of targeted tyrosine kinase inhibitor (TKI) therapies has led to long-term disease control for the vast majority of patients. Nevertheless, there are still patients that do not respond well enough to TKI therapies and available targeted therapies are also less efficient for patients in accelerated phase or blast crises. Thus, a more detailed characterization of molecular alterations that distinguish the different CML phases is still very important. We performed an in-depth bioinformatics analysis of publicly available gene expression profiles of the three CML phases. Pairwise comparisons revealed many differentially expressed genes that formed a characteristic gene expression signature, which clearly distinguished the three CML phases. Signaling pathway expression patterns were very similar between the three phases but differed strongly in the number of affected genes, which increased with the phase. Still, significant alterations of MAPK, VEGF, PI3K-Akt, adherens junction and cytokine receptor interaction signaling distinguished specific phases. Our study also suggests that one can consider the phase-wise CML development as a three rather than a two-step process. This is in accordance with the phase-specific expression behavior of 24 potential major regulators that we predicted by a network-based approach. Several of these genes are known to be involved in the accumulation of additional mutations, alterations of immune responses, deregulation of signaling pathways or may have an impact on treatment response and survival. Importantly, some of these genes have already been reported in relation to CML (e.g., AURKB, AZU1, HLA-B, HLA-DMB, PF4) and others have been found to play important roles in different leukemias (e.g., CDCA3, RPL18A, PRG3, TLX3). In addition, increased expression of BCL2 in the accelerated and blast phase indicates that venetoclax could be a potential treatment option. Moreover, a characteristic signaling pathway signature with increased expression of cytokine and ECM receptor interaction pathway genes distinguished imatinib-resistant patients from each individual CML phase. Overall, our comparative analysis contributes to an in-depth molecular characterization of similarities and differences of the CML phases and provides hints for the identification of patients that may not profit from an imatinib therapy, which could support the development of additional treatment strategies. Full article

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16 pages, 25741 KiB

Open AccessArticle

RhoGDI2-Mediated Rac1 Recruitment to Filamin A Enhances Rac1 Activity and Promotes Invasive Abilities of Gastric Cancer Cells

by Hyo-Jin Kim, Ki-Jun Ryu, Minju Kim, Taeyoung Kim, Seon-Hee Kim, Hyeontak Han, Hyemin Kim, Keun-Seok Hong, Chae Yeong Song, Yeonga Choi, Cheol Hwangbo, Kwang Dong Kim and Jiyun Yoo

Cancers 2022, 14(1), 255; https://doi.org/10.3390/cancers14010255 - 05 Jan 2022

Cited by 6 | Viewed by 2739

Abstract

Rho GDP dissociation inhibitor 2 (RhoGDI2), a regulator of Rho family GTPase, has been known to promote tumor growth and malignant progression in gastric cancer. We previously showed that RhoGDI2 positively regulates Rac1 activity and Rac1 activation is critical for RhoGDI2-induced gastric cancer [...] Read more.

Rho GDP dissociation inhibitor 2 (RhoGDI2), a regulator of Rho family GTPase, has been known to promote tumor growth and malignant progression in gastric cancer. We previously showed that RhoGDI2 positively regulates Rac1 activity and Rac1 activation is critical for RhoGDI2-induced gastric cancer cell invasion. In this study, to identify the precise molecular mechanism by which RhoGDI2 activates Rac1 activity, we performed two-hybrid screenings using yeast and found that RhoGDI2 plays an important role in the interaction between Rac1, Filamin A and Rac1 activation in gastric cancer cells. Moreover, we found that Filamin A is required for Rac1 activation and the invasive ability of gastric cancer cells. Depletion of Filamin A expression markedly reduced Rac1 activity in RhoGDI2-expressing gastric cancer cells. The migration and invasion ability of RhoGDI2-expressing gastric cancer cells also substantially decreased when Filamin A expression was depleted. Furthermore, we found that Trio, a Rac1-specific guanine nucleotide exchange factor (GEF), is critical for Rac1 activation and the invasive ability of gastric cancer cells. Therefore, we conclude that RhoGDI2 increases Rac1 activity by recruiting Rac1 to Filamin A and enhancing the interaction between Rac1 and Trio, which is critical for the invasive ability of gastric cancer cells. Full article

(This article belongs to the Special Issue Understanding Molecular Regulation of Cancer Progression and Metastasis)

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15 pages, 12064 KiB

Open AccessArticle

Reliability of Alkaline Phosphatase for Differentiating Flare Phenomenon from Disease Progression with Bone Scintigraphy

by Ji-hoon Jung, Chae-Moon Hong, Il Jo, Shin-Young Jeong, Sang-Woo Lee, Jaetae Lee and Byeong-Cheol Ahn

Cancers 2022, 14(1), 254; https://doi.org/10.3390/cancers14010254 - 05 Jan 2022

Cited by 5 | Viewed by 3954

Abstract

The flare phenomenon (FP) on bone scintigraphy after the initiation of systemic treatment seriously complicates evaluations of therapeutic response in patients with bone metastases. The aim of this study was to evaluate whether serum alkaline phosphatase (ALP) can differentiate FP from disease progression [...] Read more.

The flare phenomenon (FP) on bone scintigraphy after the initiation of systemic treatment seriously complicates evaluations of therapeutic response in patients with bone metastases. The aim of this study was to evaluate whether serum alkaline phosphatase (ALP) can differentiate FP from disease progression on bone scintigraphy in these patients. Breast or prostate cancer patients with bone metastases who newly underwent systemic therapy were reviewed. Pretreatment baseline and follow-up data, including age, pathologic factors, type of systemic therapy, radiologic and bone scintigraphy findings, and ALP levels, were obtained. Univariate and multivariate analyses of these factors were performed to predict FP. An increased extent and/or new lesions were found in 160 patients on follow-up bone scintigraphy after therapy. Among the 160 patients, 80 (50%) had an improvement on subsequent bone scintigraphy (BS), while subsequent scintigraphy also showed an increased uptake in 80 (50%, progression). Multiple regression analysis revealed that stable or decreased ALP was an independent predictor for FP (p < 0.0001). ALP was an independent predictor for FP on subgroup analysis for breast and prostate cancer (p = 0.001 and p = 0.0223, respectively). Results of the study suggest that ALP is a useful serologic marker to differentiate FP from disease progression on bone scintigraphy in patients with bone metastasis. Clinical interpretation for scintigraphic aggravation can be further improved by the ALP data and it may prevent fruitless changes of therapeutic modality by misdiagnosis of disease progression in cases of FP. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Malignant Bone Tumors)

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12 pages, 816 KiB

Open AccessArticle

Machine Learning to Discern Interactive Clusters of Risk Factors for Late Recurrence of Metastatic Breast Cancer

by Juan Luis Gomez Marti, Adam Brufsky, Alan Wells and Xia Jiang

Cancers 2022, 14(1), 253; https://doi.org/10.3390/cancers14010253 - 05 Jan 2022

Cited by 2 | Viewed by 2454

Abstract

Background: Risk of metastatic recurrence of breast cancer after initial diagnosis and treatment depends on the presence of a number of risk factors. Although most univariate risk factors have been identified using classical methods, machine-learning methods are also being used to tease out [...] Read more.

Background: Risk of metastatic recurrence of breast cancer after initial diagnosis and treatment depends on the presence of a number of risk factors. Although most univariate risk factors have been identified using classical methods, machine-learning methods are also being used to tease out non-obvious contributors to a patient’s individual risk of developing late distant metastasis. Bayesian-network algorithms can identify not only risk factors but also interactions among these risks, which consequently may increase the risk of developing metastatic breast cancer. We proposed to apply a previously developed machine-learning method to discern risk factors of 5-, 10- and 15-year metastases. Methods: We applied a previously validated algorithm named the Markov Blanket and Interactive Risk Factor Learner (MBIL) to the electronic health record (EHR)-based Lynn Sage Database (LSDB) from the Lynn Sage Comprehensive Breast Center at Northwestern Memorial Hospital. This algorithm provided an output of both single and interactive risk factors of 5-, 10-, and 15-year metastases from the LSDB. We individually examined and interpreted the clinical relevance of these interactions based on years to metastasis and reliance on interactivity between risk factors. Results: We found that, with lower alpha values (low interactivity score), the prevalence of variables with an independent influence on long-term metastasis was higher (i.e., HER2, TNEG). As the value of alpha increased to 480, stronger interactions were needed to define clusters of factors that increased the risk of metastasis (i.e., ER, smoking, race, alcohol usage). Conclusion: MBIL identified single and interacting risk factors of metastatic breast cancer, many of which were supported by clinical evidence. These results strongly recommend the development of further large data studies with different databases to validate the degree to which some of these variables impact metastatic breast cancer in the long term. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

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17 pages, 4020 KiB

Open AccessEditor’s ChoiceArticle

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression

by James Drury, Piotr G. Rychahou, Courtney O. Kelson, Mariah E. Geisen, Yuanyuan Wu, Daheng He, Chi Wang, Eun Y. Lee, B. Mark Evers and Yekaterina Y. Zaytseva

Cancers 2022, 14(1), 252; https://doi.org/10.3390/cancers14010252 - 05 Jan 2022

Cited by 25 | Viewed by 5010

Abstract

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in [...] Read more.

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36–MMP28 axis may be an effective therapeutic strategy for CRC metastasis. Full article

(This article belongs to the Special Issue Insight into Fatty Acid Metabolism in Colorectal Cancer)

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19 pages, 4440 KiB

Open AccessArticle

The Molecular Landscape of Medulloblastoma in Teenagers and Young Adults

by Omar J. Mohammed, Maria Estevez Cebrero, Omar Ahmad, Andrew Peet, Richard G. Grundy and Anbarasu Lourdusamy

Cancers 2022, 14(1), 251; https://doi.org/10.3390/cancers14010251 - 05 Jan 2022

Cited by 1 | Viewed by 2468

Abstract

Medulloblastoma (MB) is a childhood malignant brain tumour but also occurs in teenagers and young adults (TYA). Considering that MB is heterogeneous, this study aimed to define the molecular landscape of MBs in TYAs. We collated more than 2000 MB samples that included [...] Read more.

Medulloblastoma (MB) is a childhood malignant brain tumour but also occurs in teenagers and young adults (TYA). Considering that MB is heterogeneous, this study aimed to define the molecular landscape of MBs in TYAs. We collated more than 2000 MB samples that included 287 TYA patients (13–24 years). We performed computational analyses consisting of genome-wide methylation and transcriptomic profiles and developed a prognostics model for the TYAs with MB. We identified that TYAs predominantly comprised of Group 4 (40%) and Sonic Hedgehog (SHH)-activated (33%) tumours, with Wingless-type (WNT, 17%) and Group 3 (10%) being less common. TYAs with SHH tumours displayed significantly more gene expression alterations, whereas no gene was detected in the Group 4 tumours. Across MB subgroups, we identified unique and shared sets of TYA-specific differentially methylated probes and DNA-binding motifs. Finally, a 22-gene signature stratified TYA patients into high- and low-risk groups, and the prognostic significance of these risk groups persisted in multivariable regression models (P = 0.001). This study is an important step toward delineating the molecular landscape of TYAs with MB. The emergence of novel genes and pathways may provide a basis for improved clinical management of TYA with MB. Full article

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14 pages, 1475 KiB

Open AccessEditor’s ChoiceReview

Fatty Acid Metabolism in Myeloid-Derived Suppressor Cells and Tumor-Associated Macrophages: Key Factor in Cancer Immune Evasion

by Sophiya Siddiqui and Rainer Glauben

Cancers 2022, 14(1), 250; https://doi.org/10.3390/cancers14010250 - 04 Jan 2022

Cited by 17 | Viewed by 3856

Abstract

The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, [...] Read more.

The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, differentiation, and polarization from tumor suppressive into immune suppressive phenotypes. Macrophages represent one of the major immune infiltrates into TME. Blood monocyte-derived macrophages and myeloid derived suppressor cells (MDSCs) infiltrating into the TME potentiate hostile tumor progression by polarizing into immunosuppressive tumor-associated macrophages (TAMs). Recent studies in the field of immunometabolism focus on metabolic reprogramming at the TME in polarizing tumor-associated macrophages (TAMs). Lipid droplets (LD), detected in almost every eukaryotic cell type, represent the major source for intra-cellular fatty acids. Previously, LDs were mainly described as storage sites for fatty acids. However, LDs are now recognized to play an integral role in cellular signaling and consequently in inflammation and metabolism-mediated phenotypical changes in immune cells. In recent years, the role of LD dependent metabolism in macrophage functionality and phenotype has been being investigated. In this review article, we discuss fatty acids stored in LDs, their role in modulating metabolism of tumor-infiltrating immune cells and, therefore, in shaping the cancer progression. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)

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12 pages, 690 KiB

Open AccessReview

Paraneoplastic Syndromes in Patients with Keratinocyte Skin Cancer

by Christoforos Vlachos, Chrysanthi Tziortzioti and Ioannis D. Bassukas

Cancers 2022, 14(1), 249; https://doi.org/10.3390/cancers14010249 - 04 Jan 2022

Cited by 4 | Viewed by 2472

Abstract

A variety of well-characterized cutaneous paraneoplastic syndromes (PNS) are diagnosed during internal malignancies; however, the spectrum of keratinocyte skin neoplasms (KSC) related to PNS is still obscure. The aim of the present review is to compile and evaluate the literature data on PNS [...] Read more.

A variety of well-characterized cutaneous paraneoplastic syndromes (PNS) are diagnosed during internal malignancies; however, the spectrum of keratinocyte skin neoplasms (KSC) related to PNS is still obscure. The aim of the present review is to compile and evaluate the literature data on PNS associated with a keratinocyte skin neoplasm (KSC). Employing Pubmed, MEDLINE was searched for KSC-associated PNS reports. Forty relevant entries were assembled, reporting a total of 41 PNS cases associated with a KSC (34 male). No review paper compiling this topic was found. Six distinct PNS entities were identified, and malignancy associated hypercalcemia (MAH; 78%), anemia (10%) and Bazex syndrome (5%) were the most frequently reported among them. 85% of the PNS were reported in association with SCC, 10% with BCC, and the rest with adnexal tumors. The median age of the patients at the time of PNS diagnosis was 58 years (range: five–83 years). In most cases the PNS was diagnosed either concurrently or after the KSC diagnosis. KSC predisposing conditions, as scars (22%) or hidradenitis suppurativa (20%), were reported in >70% of the PNS cases. Most PNS resolved after KSC treatment. In conclusion, PNS of a rather limited spectrum of entities are reported in association with KSC. They also seem to be rare, possibly reflecting a limited capacity of KSC to provoke overt PNS. Full article

(This article belongs to the Special Issue Keratinocyte Carcinomas: Biology and Evolving Non-Invasive Management Paradigms)

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22 pages, 5901 KiB

Open AccessArticle

Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA

by Wataru Nakajima, Kai Miyazaki, Masahiro Sakaguchi, Yumi Asano, Mariko Ishibashi, Tomoko Kurita, Hiroki Yamaguchi, Hiroyuki Takei and Nobuyuki Tanaka

Cancers 2022, 14(1), 248; https://doi.org/10.3390/cancers14010248 - 04 Jan 2022

Cited by 4 | Viewed by 3122

Abstract

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and [...] Read more.

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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13 pages, 1946 KiB

Open AccessArticle

Classic Hodgkin Lymphoma Refractory for ABVD Treatment Is Characterized by Pathologically Activated Signal Transduction Pathways as Revealed by Proteomic Profiling

by Bent Honoré, Maja Dam Andersen, Diani Wilken, Peter Kamper, Francesco d’Amore, Stephen Hamilton-Dutoit and Maja Ludvigsen

Cancers 2022, 14(1), 247; https://doi.org/10.3390/cancers14010247 - 04 Jan 2022

Cited by 2 | Viewed by 2480

Abstract

In classic Hodgkin lymphoma (cHL), the tumour microenvironment (TME) is of major pathological relevance. The paucity of neoplastic cells makes it important to study the entire TME when searching for prognostic biomarkers. Cure rates in cHL have improved markedly over the last several [...] Read more.

In classic Hodgkin lymphoma (cHL), the tumour microenvironment (TME) is of major pathological relevance. The paucity of neoplastic cells makes it important to study the entire TME when searching for prognostic biomarkers. Cure rates in cHL have improved markedly over the last several decades, but patients with primary refractory disease still show inferior survival. We performed a proteomic comparison of pretreatment tumour tissue from ABVD treatment-refractory versus ABVD treatment-sensitive cHL patients, in order to identify biological differences correlating with treatment outcome. Formalin-fixed paraffin-embedded tumour tissues from 36 patients with cHL, 15 with treatment-refractory disease, and 21 with treatment-sensitive disease, were processed for proteomic investigation. Label-free quantification nano liquid chromatography tandem mass spectrometry was performed on the tissues. A total of 3920 proteins were detected and quantified between the refractory and sensitive groups. This comparison revealed several subtle but significant differences in protein expression which could identify subcluster characteristics of the refractory group. Bioinformatic analysis of the biological differences indicated that a number of pathologically activated signal transduction pathways are disturbed in ABVD treatment-refractory cHL. Full article

(This article belongs to the Special Issue Novel Markers in Lymphoma)

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11 pages, 3229 KiB

Open AccessArticle

Cause of Death, Mortality and Occult Blood in Colorectal Cancer Screening

by Lasse Kaalby, Issam Al-Najami, Ulrik Deding, Gabriele Berg-Beckhoff, Robert J. C. Steele, Morten Kobaek-Larsen, Aasma Shaukat, Morten Rasmussen and Gunnar Baatrup

Cancers 2022, 14(1), 246; https://doi.org/10.3390/cancers14010246 - 04 Jan 2022

Cited by 9 | Viewed by 2193

Abstract

Fecal hemoglobin (f-Hb) detected by the guaiac fecal occult blood test (gFOBT) may be associated with mortality and cause of death in colorectal cancer (CRC) screening participants. We investigated this association in a randomly selected population of 20,694 participants followed for 33 years. [...] Read more.

Fecal hemoglobin (f-Hb) detected by the guaiac fecal occult blood test (gFOBT) may be associated with mortality and cause of death in colorectal cancer (CRC) screening participants. We investigated this association in a randomly selected population of 20,694 participants followed for 33 years. We followed participants from the start of the Hemoccult-II CRC trial in 1985–1986 until December 2018. Data on mortality, cause of death and covariates were retrieved using Danish national registers. We conducted multivariable Cox regressions with time-varying exposure, reporting results as crude and adjusted hazard ratios (aHRs). We identified 1766 patients with at least one positive gFOBT, 946 of whom died in the study period. Most gFOBT-positive participants (93.23%) died of diseases unrelated to CRC and showed higher non-CRC mortality than gFOBT-negative participants (aHR: 1.20, 95% CI 1.10–1.30). Positive gFOBT participants displayed a modest increase in all-cause (aHR: 1.28, 95% CI: 1.18–1.38), CRC (aHR: 4.07, 95% CI: 3.00–5.56), cardiovascular (aHR: 1.22, 95% CI: 1.07–1.39) and endocrine and hematological mortality (aHR: 1.58, 95% CI: 1.19–2.10). In conclusion, we observed an association between positive gFOBT, cause of death and mortality. The presence of f-Hb in the gFOBT might indicate the presence of systemic diseases. Full article

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16 pages, 1807 KiB

Open AccessReview

Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

by Ruggiero Gorgoglione, Valeria Impedovo, Christopher L. Riley, Deborah Fratantonio, Stefano Tiziani, Luigi Palmieri, Vincenza Dolce and Giuseppe Fiermonte

Cancers 2022, 14(1), 245; https://doi.org/10.3390/cancers14010245 - 04 Jan 2022

Cited by 14 | Viewed by 4461

Abstract

Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate [...] Read more.

Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention. Full article

(This article belongs to the Special Issue The Role of Mitochondrial Ion Channels and Transporters in Cancer Development and Progression)

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14 pages, 959 KiB

Open AccessArticle

Predicting Frailty and Geriatric Interventions in Older Cancer Patients: Performance of Two Screening Tools for Seven Frailty Definitions—ELCAPA Cohort

by Claudia Martinez-Tapia, Marie Laurent, Elena Paillaud, Philippe Caillet, Emilie Ferrat, Jean-Léon Lagrange, Jean-Paul Rwabihama, Mylène Allain, Anne Chahwakilian, Pascaline Boudou-Rouquette, Sylvie Bastuji-Garin and Etienne Audureau

Cancers 2022, 14(1), 244; https://doi.org/10.3390/cancers14010244 - 04 Jan 2022

Cited by 8 | Viewed by 2650

Abstract

Screening tools have been developed to identify patients warranting a complete geriatric assessment (GA). However, GA lacks standardization and does not capture important aspects of geriatric oncology practice. We measured and compared the diagnostic performance of screening tools G8 and modified G8 according [...] Read more.

Screening tools have been developed to identify patients warranting a complete geriatric assessment (GA). However, GA lacks standardization and does not capture important aspects of geriatric oncology practice. We measured and compared the diagnostic performance of screening tools G8 and modified G8 according to multiple clinically relevant reference standards. We included 1136 cancer patients ≥ 70 years old referred for GA (ELCAPA cohort; median age, 80 years; males, 52%; main locations: digestive (36.3%), breast (16%), and urinary tract (14.8%); metastases, 43.5%). Area under the receiver operating characteristic curve (AUROC) estimates were compared between both tools against: (1) the detection of ≥1 or (2) ≥2 GA impairments, (3) the prescription of ≥1 geriatric intervention and the identification of an unfit profile according to (4) a latent class typology, expert-based classifications from (5) Balducci, (6) the International Society of Geriatric Oncology task force (SIOG), or using (7) a GA frailty index according to the Rockwood accumulation of deficits principle. AUROC values were ≥0.80 for both tools under all tested definitions. They were statistically significantly higher for the modified G8 for six reference standards: ≥1 GA impairment (0.93 vs. 0.89), ≥2 GA impairments (0.90 vs. 0.87), ≥1 geriatric intervention (0.85 vs. 0.81), unfit according to Balducci (0.86 vs. 0.80) and SIOG classifications (0.88 vs. 0.83), and according to the GA frailty index (0.86 vs. 0.84). Our findings demonstrate the robustness of both screening tools against different reference standards, with evidence of better diagnostic performance of the modified G8. Full article

(This article belongs to the Special Issue Advances in Geriatric Oncology: Exploring Practical Ways to Optimize Treatment in Older Patients with Cancer)

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18 pages, 26237 KiB

Open AccessArticle

Comparative O-GlcNAc Proteomic Analysis Reveals a Role of O-GlcNAcylated SAM68 in Lung Cancer Aggressiveness

by Chia-Hung Lin, Chen-Chung Liao, Shu-Ying Wang, Chia-Yi Peng, Yi-Chen Yeh, Mei-Yu Chen and Teh-Ying Chou

Cancers 2022, 14(1), 243; https://doi.org/10.3390/cancers14010243 - 04 Jan 2022

Cited by 10 | Viewed by 2705

Abstract

O-GlcNAcylation is a reversible and dynamic post-translational protein modification catalyzed by O-GlcNAc transferase (OGT). Despite the reported association of O-GlcNAcylation with cancer metastasis, the O-GlcNAc proteome profile for cancer aggressiveness remains largely uncharacterized. Here, we report our comparative O [...] Read more.

O-GlcNAcylation is a reversible and dynamic post-translational protein modification catalyzed by O-GlcNAc transferase (OGT). Despite the reported association of O-GlcNAcylation with cancer metastasis, the O-GlcNAc proteome profile for cancer aggressiveness remains largely uncharacterized. Here, we report our comparative O-GlcNAc proteome profiling of two differentially invasive lung adenocarcinoma cell lines, which identified 158 down-regulated and 106 up-regulated candidates in highly invasive cells. Among these differential proteins, a nuclear RNA-binding protein, SAM68 (SRC associated in mitosis of 68 kDa), was further investigated. Results showed that SAM68 is O-GlcNAcylated and may interact with OGT in the nucleus. Eleven O-GlcNAcylation sites were identified, and data from mutant analysis suggested that multiple serine residues in the N-terminal region are important for O-GlcNAcylation and the function of SAM68 in modulating cancer cell migration and invasion. Analysis of clinical specimens found that high SAM68 expression was associated with late cancer stages, and patients with high-OGT/high-SAM68 expression in their tumors had poorer overall survival compared to those with low-OGT/low-SAM68 expression. Our study revealed an invasiveness-associated O-GlcNAc proteome profile and connected O-GlcNAcylated SAM68 to lung cancer aggressiveness. Full article

(This article belongs to the Special Issue O-GlcNAcylation and Cancer)

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12 pages, 292 KiB

Open AccessReview

Recent Advances in the Diagnosis and Management of Multiple Primary Lung Cancer

by Chi-Lu Chiang, Ping-Chung Tsai, Yi-Chen Yeh, Yuan-Hung Wu, Han-Shui Hsu and Yuh-Min Chen

Cancers 2022, 14(1), 242; https://doi.org/10.3390/cancers14010242 - 04 Jan 2022

Cited by 15 | Viewed by 3344

Abstract

With the wide application of computed tomography in lung cancer screening, the incidence of multiple primary lung cancer (MPLC) has been increasingly reported. Despite the established criteria, the differentiation between MPLC and intrapulmonary metastasis remains challenging. Although histologic features are helpful in some [...] Read more.

With the wide application of computed tomography in lung cancer screening, the incidence of multiple primary lung cancer (MPLC) has been increasingly reported. Despite the established criteria, the differentiation between MPLC and intrapulmonary metastasis remains challenging. Although histologic features are helpful in some circumstances, a molecular analysis is often needed. The application of next-generation sequencing could aid in distinguishing MPLCs from intrapulmonary metastasis, decreasing ambiguity. For MPLC management, surgery with lobectomy is the main operation method. Limited resection does not appear to negatively affect survival, and it is a reasonable alternative. Stereotactic ablative radiotherapy (SABR) has become a standard of care for patients refusing surgery or for those with medically inoperable early-stage lung cancer. However, the efficacy of SABR in MPLC management could only be found in retrospective series. Other local ablation techniques are an emerging alternative for the control of residual lesions. Furthermore, systemic therapies, such as targeted therapy for oncogene-addicted patients, and immunotherapy have shown promising results in MPLC management after resection. In this paper, the recent advances in the diagnosis and management of MPLC are reviewed. Full article

(This article belongs to the Collection Diagnosis and Treatment of Primary and Secondary Lung Cancers)

13 pages, 2379 KiB

Open AccessEditor’s ChoiceArticle

Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases

by Valentina Giannini, Laura Pusceddu, Arianna Defeudis, Giulia Nicoletti, Giovanni Cappello, Simone Mazzetti, Andrea Sartore-Bianchi, Salvatore Siena, Angelo Vanzulli, Francesco Rizzetto, Elisabetta Fenocchio, Luca Lazzari, Alberto Bardelli, Silvia Marsoni and Daniele Regge

Cancers 2022, 14(1), 241; https://doi.org/10.3390/cancers14010241 - 04 Jan 2022

Cited by 15 | Viewed by 5748

Abstract

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after [...] Read more.

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R−) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R− lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

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10 pages, 4537 KiB

Open AccessArticle

A New Approach for a Safe and Reproducible Seeds Positioning for Diffusing Alpha-Emitters Radiation Therapy of Squamous Cell Skin Cancer: A Feasibility Study

by Giacomo Feliciani, Salvatore Roberto Bellia, Massimo Del Duca, Giorgio Mazzotti, Manuela Monti, Ignazio Stanganelli, Yona Keisari, Itzhak Kelson, Aron Popovtzer, Antonino Romeo and Anna Sarnelli

Cancers 2022, 14(1), 240; https://doi.org/10.3390/cancers14010240 - 04 Jan 2022

Cited by 4 | Viewed by 2443

Abstract

The purpose of this study is to discuss how to use an external radio-opaque template in the Diffusing Alpha-emitters Radiation Therapy (DaRT) technique’s pre-planning and treatment stages. This device would help to determine the proper number of sources for tumour coverage, accounting for [...] Read more.

The purpose of this study is to discuss how to use an external radio-opaque template in the Diffusing Alpha-emitters Radiation Therapy (DaRT) technique’s pre-planning and treatment stages. This device would help to determine the proper number of sources for tumour coverage, accounting for subcutaneous invasion and augmenting DaRT safety. The procedure will be carried out in a first phase on a phantom and then applied to a clinical case. A typical DaRT procedure workflow comprises steps like tumour measurements and delineation, source number assessment, and therapy administration. As a first step, an adhesive fiberglass mesh (spaced by 2 mm) tape was applied on the skin of the patient and employed as frame of reference. A physician contoured the lesion and marked the entrance points for the needles with a radio opaque ink marker. According to the radio opaque marks and metabolic uptake the clinical target volume was defined, and with a commercial brachytherapy treatment planning system (TPS) it was possible to simulate and adjust the spatial seeds distribution. After the implant procedure a CT was again performed to check the agreement between simulations and seeds positions. With the procedure described above it was possible to simulate a DaRT procedure on a phantom in order to train physicians and subsequently apply the novel approach on patients, outlining the major issues involved in the technique. The present work innovates and supports DaRT technique for the treatment of cutaneous cancers, improving its efficacy and safety. Full article

(This article belongs to the Collection Advances in Diagnostic and Interventional Radiology in Oncology)

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14 pages, 307 KiB

Open AccessReview

Prognostic Factors for Localized Clear Cell Renal Cell Carcinoma and Their Application in Adjuvant Therapy

by Kalle E. Mattila, Paula Vainio and Panu M. Jaakkola

Cancers 2022, 14(1), 239; https://doi.org/10.3390/cancers14010239 - 04 Jan 2022

Cited by 13 | Viewed by 3062

Abstract

Approximately 20% of patients with renal cell carcinoma (RCC) present with primarily metastatic disease and over 30% of patients with localized RCC will develop distant metastases later, after complete resection of the primary tumor. Accurate postoperative prognostic models are essential for designing personalized [...] Read more.

Approximately 20% of patients with renal cell carcinoma (RCC) present with primarily metastatic disease and over 30% of patients with localized RCC will develop distant metastases later, after complete resection of the primary tumor. Accurate postoperative prognostic models are essential for designing personalized surveillance programs, as well as for designing adjuvant therapy and trials. Several clinical and histopathological prognostic factors have been identified and adopted into prognostic algorithms to assess the individual risk for disease recurrence after radical or partial nephrectomy. However, the prediction accuracy of current prognostic models has been studied in retrospective patient cohorts and the optimal set of prognostic features remains unclear. In addition to traditional histopathological prognostic factors, novel biomarkers, such as gene expression profiles and circulating tumor DNA, are extensively studied to supplement existing prognostic algorithms to improve their prediction accuracy. Here, we aim to give an overview of existing prognostic features and prediction models for localized postoperative clear cell RCC and discuss their role in the adjuvant therapy trials. The results of ongoing placebo-controlled adjuvant therapy trials may elucidate prognostic factors and biomarkers that help to define patients at high risk for disease recurrence. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

28 pages, 2755 KiB

Open AccessReview

The Functional Role of Extracellular Matrix Proteins in Cancer

by Nadezhda V. Popova and Manfred Jücker

Cancers 2022, 14(1), 238; https://doi.org/10.3390/cancers14010238 - 04 Jan 2022

Cited by 59 | Viewed by 8187

Abstract

The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different [...] Read more.

The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells. Full article

(This article belongs to the Special Issue Bioengineering the Cellular and Matrix Microenvironment of the Tumor-Stroma)

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21 pages, 3679 KiB

Open AccessArticle

Comprehensive Pan-Cancer Analyses of Pyroptosis-Related Genes to Predict Survival and Immunotherapeutic Outcome

by Qilin Wang, Qian Liu, Sihan Qi, Junyou Zhang, Xian Liu, Xin Li and Chunyan Li

Cancers 2022, 14(1), 237; https://doi.org/10.3390/cancers14010237 - 04 Jan 2022

Cited by 8 | Viewed by 3374

Abstract

Pyroptosis is a newly characterized type of programmed cell death. However, its function in cancer progression and its response to treatments remain controversial. Here, we extensively and systematically compiled genes associated with pyroptosis, integrated multiomics data and clinical data across 31 cancer types [...] Read more.

Pyroptosis is a newly characterized type of programmed cell death. However, its function in cancer progression and its response to treatments remain controversial. Here, we extensively and systematically compiled genes associated with pyroptosis, integrated multiomics data and clinical data across 31 cancer types from The Cancer Genome Atlas, and delineated the global alterations in PRGs at the transcriptional level. The underlying transcriptional regulations by copy number variation, miRNAs, and enhancers were elucidated by integrating data from the Genotype-Tissue Expression and International Cancer Genome Consortium. A prognostic risk model, based on the expression of PRGs across 31 cancer types, was constructed. To investigate the role of pyroptosis in immunotherapy, we found five PRGs associated with effectiveness by exploring the RNA-Seq data of patients with immunotherapy, and further identified two small-molecule compounds that are potentially beneficial for immunotherapy. For the first time, from a pyroptosis standpoint, this study establishes a novel strategy to predict cancer patient survival and immunotherapeutic outcomes. Full article

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11 pages, 1245 KiB

Open AccessArticle

BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX with Pancreatic Ductal Adenocarcinoma in Korean Patients

by Ji Hoon Park, Jung Hyun Jo, Sung Ill Jang, Moon Jae Chung, Jeong Youp Park, Seungmin Bang, Seung Woo Park, Si Young Song, Hee Seung Lee and Jae Hee Cho

Cancers 2022, 14(1), 236; https://doi.org/10.3390/cancers14010236 - 04 Jan 2022

Cited by 7 | Viewed by 2389

Abstract

We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 [...] Read more.

We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response. Full article

(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)

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15 pages, 5477 KiB

Open AccessArticle

Hyperfractionated Treatment with ¹⁷⁷Lu-Octreotate Increases Tumor Response in Human Small-Intestine Neuroendocrine GOT1 Tumor Model

by Mikael Elvborn, Emman Shubbar and Eva Forssell-Aronsson

Cancers 2022, 14(1), 235; https://doi.org/10.3390/cancers14010235 - 04 Jan 2022

Cited by 2 | Viewed by 2251

Abstract

Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using ¹⁷⁷Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The [...] Read more.

Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using ¹⁷⁷Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with ¹⁷⁷Lu-octreotate. BALB/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30–120 MBq of ¹⁷⁷Lu-octreotate: 1 × 30, 2 × 15, 1 × 60, 2 × 30, 1 × 120, 2 × 60, or 3 × 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 × 15 = 30 and 1 × 30 MBq ¹⁷⁷Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 × 30 = 60 and 1 × 60 MBq ¹⁷⁷Lu-octreotate, respectively. After 120 MBq ¹⁷⁷Lu-octreotate, given as 1–3 fractions, the mean tumor volume was reduced by 91–97%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20–25% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of ¹⁷⁷Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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18 pages, 1653 KiB

Open AccessReview

Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma

by Silvina Odete Bustos, Nathalia Leal Santos, Roger Chammas and Luciana Nogueira de Sousa Andrade

Cancers 2022, 14(1), 234; https://doi.org/10.3390/cancers14010234 - 04 Jan 2022

Cited by 7 | Viewed by 3757

Abstract

Melanoma is the most aggressive skin cancer characterized by high mutational burden and large heterogeneity. Cancer cells are surrounded by a complex environment, critical to tumor establishment and progression. Thus, tumor-associated stromal components can sustain tumor demands or impair cancer cell progression. One [...] Read more.

Melanoma is the most aggressive skin cancer characterized by high mutational burden and large heterogeneity. Cancer cells are surrounded by a complex environment, critical to tumor establishment and progression. Thus, tumor-associated stromal components can sustain tumor demands or impair cancer cell progression. One way to manage such processes is through the regulation of autophagy, both in stromal and tumor cells. Autophagy is a catabolic mechanism that provides nutrients and energy, and it eliminates damaged organelles by degradation and recycling of cellular elements. Besides this primary function, autophagy plays multiple roles in the tumor microenvironment capable of affecting cell fate. Evidence demonstrates the existence of novel branches in the autophagy system related to cytoplasmic constituent’s secretion. Hence, autophagy-dependent secretion assembles a tangled network of signaling that potentially contributes to metabolism reprogramming, immune regulation, and tumor progression. Here, we summarize the current awareness regarding secretory autophagy and the intersection with exosome biogenesis and release in melanoma and their role in tumor resistance. In addition, we present and discuss data from public databases concerning autophagy and exosome-related genes as important mediators of melanoma behavior. Finally, we will present the main challenges in the field and strategies to translate most of the pre-clinical findings to clinical practice. Full article

(This article belongs to the Special Issue Role of Autophagy in the Interactions between the Tumor and the Microenvironment)

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13 pages, 1150 KiB

Open AccessArticle

Circulating Cell-Free DNA-Based Comprehensive Molecular Analysis of Biliary Tract Cancers Using Next-Generation Sequencing

by Szilvia Lilla Csoma, Judit Bedekovics, Gergő Veres, Anita Árokszállási, Csilla András, Gábor Méhes and Attila Mokánszki

Cancers 2022, 14(1), 233; https://doi.org/10.3390/cancers14010233 - 04 Jan 2022

Cited by 13 | Viewed by 2695

Abstract

Biliary tract cancer (BTC) is a rare malignancy with a long disease course and an overall poor prognosis. Despite multiple chemotherapy agents, there is no defined second-line treatment opportunity for advanced BTCs. In the era of precision oncology, NGS plays an important role [...] Read more.

Biliary tract cancer (BTC) is a rare malignancy with a long disease course and an overall poor prognosis. Despite multiple chemotherapy agents, there is no defined second-line treatment opportunity for advanced BTCs. In the era of precision oncology, NGS plays an important role in identifying mutations that may predict the molecular pathomechanism and manage the BTC therapy. The peripheral blood liquid biopsy (LB) of cancer patients represents variable amounts of cell-free DNA (cfDNA) released from tumor foci of any anatomical location. Our study aimed to identify somatic mutations and tumor variant burden (TVB) in cell-free and matched tumor DNA. We found a positive correlation between the estimated tumor volume and cfDNA yield (r = 0.9326, p < 0.0001). Comparing tissue and LB results, similar TVB was observed. SNVs were proven in 84% of the cases, while in two cases, only the LB sample was informative for molecular analysis. The most important aberrations in BTCs, such as FGFR2, IDH1, IDH2, KRAS, and TP53, could be detected in matched LB samples. Our prospective study demonstrates a minimally invasive testing approach to identify molecular genetic alterations in cholangiocarcinoma and gallbladder cancers. Clinical applications of cfDNA reflect by capturing the outstanding spatial tumor heterogeneity and guarantee novel aspects for the precision oncology treatment. Full article

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