Biomarkers of Tumor Metastasis and Invasiveness

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 32747

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Guest Editor
Université d’Angers, Inserm, CRCINA, F-44000 Nantes, France
Interests: cancer invasiveness; quantitative proteomics; EMT; senescence escape
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Guest Editor
Research Unit, Oncology Division, Hospital Universitario Lucus Augusti (HULA), 27003 Lugo, Spain
Interests: circulating biomarkers; proteomics; nanomaterials; oncology; diagnosis; prognosis; prediction; therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The molecular characterization of tumors, investigated particularly through proteogenomic analyses, has led to a revolution in cancer research. Over the last decade, the development of quantitative proteomics, together with other major technological breakthroughs, has identified candidate biomarkers for diagnosis, prognosis, and drug efficacy/resistance. These improvements have allowed researchers to explore the capability of cancer cells to invade, metastasize, and finally destroy normal tissues and organs. In parallel, new hypotheses have been formulated, and the means cancer cells use to exploit their surrounding environment have started to be deciphered, leading to new therapeutic approaches.

This Special Issue aims to cover all these aspects, revealing new recent insights into the molecular networks controlling the tumor invasiveness process, dynamic interactions between cancer cells and the host stroma, stemness and the epithelial-to-mesenchymal transition, and the links between inflammation and tumor metastasis.

The scope is extended to studies on all cancer histological types (original research articles and reviews) conducted on experimental tumor models, tumor samples, and/or biofluids from patients with cancer.

We look forward to receiving your contributions.

Dr. Daniel L. Pouliquen
Dr. Cristina Núñez González
Guest Editors

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Published Papers (18 papers)

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Editorial

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4 pages, 223 KiB  
Editorial
Biomarkers of Tumor Metastasis and Invasiveness
by Daniel L. Pouliquen and Cristina Núñez González
Cancers 2023, 15(20), 5000; https://doi.org/10.3390/cancers15205000 - 16 Oct 2023
Viewed by 868
Abstract
The identification of proteins as new cancer diagnostic and prognostic biomarkers continues to attract considerable attention in the oncology literature, especially in the context of invasion and metastasis activation process [...] Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)

Research

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15 pages, 1261 KiB  
Article
IMP3 Expression as a Potential Tumour Marker in High-Risk Localisations of Cutaneous Squamous Cell Carcinoma: IMP3 in Metastatic cSCC
by Maurice Klein, Merle Wefers, Christian Hallermann, Henrike J. Fischer, Frank Hölzle and Kai Wermker
Cancers 2023, 15(16), 4087; https://doi.org/10.3390/cancers15164087 - 14 Aug 2023
Cited by 1 | Viewed by 873
Abstract
Background: High IMP3 expression is correlated with a worse outcome. Until now, there have been no data about IMP3 expression and clinical outcome for high-risk localisation of squamous cell carcinoma of the skin (cSCC). Methods: One-hundred twenty-two patients with cSCC of the lip [...] Read more.
Background: High IMP3 expression is correlated with a worse outcome. Until now, there have been no data about IMP3 expression and clinical outcome for high-risk localisation of squamous cell carcinoma of the skin (cSCC). Methods: One-hundred twenty-two patients with cSCC of the lip and ear were included, and IMP3 expression in the tumours was immunohistochemically assessed in different evaluation approaches. Subsequently, subgroups were analysed in a matched pair approach and correlated with clinical pathologic parameters. In the following, different IMP3 analysis methods were tested for clinical suitability. Results: We found a significant correlation between IMP3 expression and risk for lymph node metastasis, local relapse, and progression-free survival. Conclusions: On basis of our data, we suggest a prognostic benefit cutoff value for high (>50%) and low (<50%) IMP3 expression. Thus, IMP3 expression has a high scientific potential for further studies and could potentially be used as a prognostic marker in diagnostic and therapeutic decision-making. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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22 pages, 3687 KiB  
Article
Exosome-Mediated Activation of the Prostasin-Matriptase Serine Protease Cascade in B Lymphoma Cells
by Li-Mei Chen and Karl X. Chai
Cancers 2023, 15(15), 3848; https://doi.org/10.3390/cancers15153848 - 28 Jul 2023
Cited by 1 | Viewed by 971
Abstract
Prostasin and matriptase are extracellular membrane serine proteases with opposing effects in solid epithelial tumors. Matriptase is an oncoprotein that promotes tumor initiation and progression, and prostasin is a tumor suppressor that reduces tumor invasion and metastasis. Previous studies have shown that a [...] Read more.
Prostasin and matriptase are extracellular membrane serine proteases with opposing effects in solid epithelial tumors. Matriptase is an oncoprotein that promotes tumor initiation and progression, and prostasin is a tumor suppressor that reduces tumor invasion and metastasis. Previous studies have shown that a subgroup of Burkitt lymphoma have high levels of ectopic matriptase expression but no prostasin. Reducing the matriptase level via small interfering RNAs in B lymphoma cells impeded tumor xenograft growth in mice. Here, we report a novel approach to matriptase regulation in B cancer cells by prostasin via exosomes to initiate a prostasin–matriptase protease activation cascade. The activation and shedding of matriptase were monitored by measuring its quantity and trypsin-like serine protease activity in conditioned media. Sustained activation of the protease cascade in the cells was achieved by the stable expression of prostasin. The B cancer cells with prostasin expression presented phenotypes consistent with its tumor suppressor role, such as reduced growth and increased apoptosis. Prostasin exosomes could be developed as an agent to initiate the prostasin–matriptase cascade for treating B lymphoma with further studies in animal models. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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25 pages, 3374 KiB  
Article
Proteomic and Metabolomic Analysis of Bone Marrow and Plasma from Patients with Extramedullary Multiple Myeloma Identifies Distinct Protein and Metabolite Signatures
by Katie Dunphy, Despina Bazou, Michael Henry, Paula Meleady, Juho J. Miettinen, Caroline A. Heckman, Paul Dowling and Peter O’Gorman
Cancers 2023, 15(15), 3764; https://doi.org/10.3390/cancers15153764 - 25 Jul 2023
Cited by 2 | Viewed by 1711
Abstract
Multiple myeloma (MM) is an incurable haematological malignancy of plasma cells in the bone marrow. In rare cases, an aggressive form of MM called extramedullary multiple myeloma (EMM) develops, where myeloma cells enter the bloodstream and colonise distal organs or soft tissues. This [...] Read more.
Multiple myeloma (MM) is an incurable haematological malignancy of plasma cells in the bone marrow. In rare cases, an aggressive form of MM called extramedullary multiple myeloma (EMM) develops, where myeloma cells enter the bloodstream and colonise distal organs or soft tissues. This variant is associated with refractoriness to conventional therapies and a short overall survival. The molecular mechanisms associated with EMM are not yet fully understood. Here, we analysed the proteome of bone marrow mononuclear cells and blood plasma from eight patients (one serial sample) with EMM and eight patients without extramedullary spread. The patients with EMM had a significantly reduced overall survival with a median survival of 19 months. Label-free mass spectrometry revealed 225 proteins with a significant differential abundance between bone marrow mononuclear cells (BMNCs) isolated from patients with MM and EMM. This plasma proteomics analysis identified 22 proteins with a significant differential abundance. Three proteins, namely vascular cell adhesion molecule 1 (VCAM1), pigment epithelium derived factor (PEDF), and hepatocyte growth factor activator (HGFA), were verified as the promising markers of EMM, with the combined protein panel showing excellent accuracy in distinguishing EMM patients from MM patients. Metabolomic analysis revealed a distinct metabolite signature in EMM patient plasma compared to MM patient plasma. The results provide much needed insight into the phenotypic profile of EMM and in identifying promising plasma-derived markers of EMM that may inform novel drug development strategies. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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13 pages, 2258 KiB  
Article
Gene Expression Analysis Links Autocrine Vasoactive Intestinal Peptide and ZEB1 in Gastrointestinal Cancers
by Ishani H. Rao, Edmund K. Waller, Rohan K. Dhamsania and Sanjay Chandrasekaran
Cancers 2023, 15(13), 3284; https://doi.org/10.3390/cancers15133284 - 22 Jun 2023
Cited by 1 | Viewed by 1176
Abstract
VIP (vasoactive intestinal peptide) is a 28-amino acid peptide hormone expressed by cancer and the healthy nervous system, digestive tract, cardiovascular, and immune cell tissues. Many cancers express VIP and its surface receptors VPAC1 and VPAC2, but the role of autocrine VIP signaling [...] Read more.
VIP (vasoactive intestinal peptide) is a 28-amino acid peptide hormone expressed by cancer and the healthy nervous system, digestive tract, cardiovascular, and immune cell tissues. Many cancers express VIP and its surface receptors VPAC1 and VPAC2, but the role of autocrine VIP signaling in cancer as a targetable prognostic and predictive biomarker remains poorly understood. Therefore, we conducted an in silico gene expression analysis to study the mechanisms of autocrine VIP signaling in cancer. VIP expression from TCGA PANCAN tissue samples was analyzed against the expression levels of 760 cancer-associated genes. Of the 760 genes, 10 (MAPK3, ZEB1, TEK, NOS2, PTCH1 EIF4G1, GMPS, CDK2, RUVBL1, and TIMELESS) showed statistically meaningful associations with the VIP (Pearson’s R-coefficient > |0.3|; p < 0.05) across all cancer histologies. The strongest association with the VIP was for the epithelial–mesenchymal transition regulator ZEB1 in gastrointestinal malignancies. Similar positive correlations between the VIP and ZEB1 expression were also observed in healthy gastrointestinal tissues. Gene set analysis indicates the VIP is involved in the EMT and cell cycle pathways, and a high VIP and ZEB1 expression is associated with higher median estimate and stromal scores These findings uncover novel mechanisms for VIP- signaling in cancer and specifically suggest a role for VIP as a biomarker of ZEB1-mediated EMT. Further studies are warranted to characterize the specific mechanism of this interaction. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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17 pages, 9697 KiB  
Article
Long-Chain Acyl Coenzyme A Dehydrogenase, a Key Player in Metabolic Rewiring/Invasiveness in Experimental Tumors and Human Mesothelioma Cell Lines
by Daniel L. Pouliquen, Giacomo Ortone, Letizia Rumiano, Alice Boissard, Cécile Henry, Stéphanie Blandin, Catherine Guette, Chiara Riganti and Joanna Kopecka
Cancers 2023, 15(11), 3044; https://doi.org/10.3390/cancers15113044 - 3 Jun 2023
Cited by 2 | Viewed by 1540
Abstract
Cross-species investigations of cancer invasiveness are a new approach that has already identified new biomarkers which are potentially useful for improving tumor diagnosis and prognosis in clinical medicine and veterinary science. In this study, we combined proteomic analysis of four experimental rat malignant [...] Read more.
Cross-species investigations of cancer invasiveness are a new approach that has already identified new biomarkers which are potentially useful for improving tumor diagnosis and prognosis in clinical medicine and veterinary science. In this study, we combined proteomic analysis of four experimental rat malignant mesothelioma (MM) tumors with analysis of ten patient-derived cell lines to identify common features associated with mitochondrial proteome rewiring. A comparison of significant abundance changes between invasive and non-invasive rat tumors gave a list of 433 proteins, including 26 proteins reported to be exclusively located in mitochondria. Next, we analyzed the differential expression of genes encoding the mitochondrial proteins of interest in five primary epithelioid and five primary sarcomatoid human MM cell lines; the most impressive increase was observed in the expression of the long-chain acyl coenzyme A dehydrogenase (ACADL). To evaluate the role of this enzyme in migration/invasiveness, two epithelioid and two sarcomatoid human MM cell lines derived from patients with the highest and lowest overall survival were studied. Interestingly, sarcomatoid vs. epithelioid cell lines were characterized by higher migration and fatty oxidation rates, in agreement with ACADL findings. These results suggest that evaluating mitochondrial proteins in MM specimens might identify tumors with higher invasiveness. Data are available via ProteomeXchange with the dataset identifier PXD042942. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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0 pages, 4766 KiB  
Article
Therapeutic Potential of BAY-117082, a Selective NLRP3 Inflammasome Inhibitor, on Metastatic Evolution in Human Oral Squamous Cell Carcinoma (OSCC)
by Giovanna Casili, Sarah Adriana Scuderi, Marika Lanza, Alessia Filippone, Deborah Mannino, Raffaella Giuffrida, Cristina Colarossi, Marzia Mare, Anna Paola Capra, Federica De Gaetano, Marco Portelli, Angela Militi, Salvatore Cuzzocrea, Irene Paterniti and Emanuela Esposito
Cancers 2023, 15(10), 2796; https://doi.org/10.3390/cancers15102796 - 17 May 2023
Cited by 2 | Viewed by 1330 | Correction
Abstract
Oral squamous cell carcinoma (OSCC) is a commonly occurring head and neck cancer and it is characterized by a high metastasis grade. The aim of this study was to evaluate for the first time the effect of BAY-117082, a selective NLRP3 inflammasome inhibitor, [...] Read more.
Oral squamous cell carcinoma (OSCC) is a commonly occurring head and neck cancer and it is characterized by a high metastasis grade. The aim of this study was to evaluate for the first time the effect of BAY-117082, a selective NLRP3 inflammasome inhibitor, in an in vivo orthotopic model of OSCC and its role in the invasiveness and metastasis processes in neighbor organs such as lymph node, lung, and spleen tissues. Our results demonstrated that BAY-117082 treatment, at doses of 2.5 mg/kg and 5 mg/kg, was able to significantly reduce the presence of microscopic tumor islands and nuclear pleomorphism in tongue tissues and modulate the NLRP3 inflammasome pathway activation in tongue tissues, as well as in metastatic organs such as lung and spleen. Additionally, BAY-117082 treatment modulated the epithelial–mesenchymal transition (EMT) process in tongue tissue as well as in metastatic organs such as lymph node, lung, and spleen, also reducing the expression of matrix metalloproteinases (MMPs), particularly MMP2 and MMP9, markers of cell invasion and migration. In conclusion, the obtained data demonstrated that BAY-117082 at doses of 2.5 mg/kg and 5 mg/kg were able to reduce the tongue tumor area as well as the degree of metastasis in lymph node, lung, and spleen tissues through the NLRP3 inflammasome pathway inhibition. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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12 pages, 831 KiB  
Article
Preoperative CA125 Significantly Improves Risk Stratification in High-Grade Endometrial Cancer
by Marike S. Lombaers, Karlijn M. C. Cornel, Nicole C. M. Visser, Johan Bulten, Heidi V. N. Küsters-Vandevelde, Frédéric Amant, Dorry Boll, Peter Bronsert, Eva Colas, Peggy M. A. J. Geomini, Antonio Gil-Moreno, Dennis van Hamont, Jutta Huvila, Camilla Krakstad, Arjan A. Kraayenbrink, Martin Koskas, Gemma Mancebo, Xavier Matías-Guiu, Huy Ngo, Brenda M. Pijlman, Maria Caroline Vos, Vit Weinberger, Marc P. L. M. Snijders, Sebastiaan W. van Koeverden, ENITEC-Consortium, Ingfrid S. Haldorsen, Casper Reijnen and Johanna M. A. Pijnenborgadd Show full author list remove Hide full author list
Cancers 2023, 15(9), 2605; https://doi.org/10.3390/cancers15092605 - 4 May 2023
Cited by 2 | Viewed by 1697
Abstract
Patients with high-grade endometrial carcinoma (EC) have an increased risk of tumor spread and lymph node metastasis (LNM). Preoperative imaging and CA125 can be used in work-up. As data on cancer antigen 125 (CA125) in high-grade EC are limited, we aimed to study [...] Read more.
Patients with high-grade endometrial carcinoma (EC) have an increased risk of tumor spread and lymph node metastasis (LNM). Preoperative imaging and CA125 can be used in work-up. As data on cancer antigen 125 (CA125) in high-grade EC are limited, we aimed to study primarily the predictive value of CA125, and secondarily the contributive value of computed tomography (CT) for advanced stage and LNM. Patients with high-grade EC (n = 333) and available preoperative CA125 were included retrospectively. The association of CA125 and CT findings with LNM was analyzed by logistic regression. Elevated CA125 ((>35 U/mL), (35.2% (68/193)) was significantly associated with stage III-IV disease (60.3% (41/68)) compared with normal CA125 (20.8% (26/125), [p < 0.001]), and with reduced disease-specific—(DSS) (p < 0.001) and overall survival (OS) (p < 0.001). The overall accuracy of predicting LNM by CT resulted in an area under the curve (AUC) of 0.623 (p < 0.001) independent of CA125. Stratification by CA125 resulted in an AUC of 0.484 (normal), and 0.660 (elevated). In multivariate analysis elevated CA125, non-endometrioid histology, pathological deep myometrial invasion ≥50%, and cervical involvement were significant predictors of LNM, whereas suspected LNM on CT was not. This shows that elevated CA125 is a relevant independent predictor of advanced stage and outcome specifically in high-grade EC. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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19 pages, 4684 KiB  
Article
CD19 (+) B Cell Combined with Prognostic Nutritional Index Predicts the Clinical Outcomes of Patients with Gastric Cancer Who Underwent Surgery
by Hao Sun, Huibo Wang, Hongming Pan, Yanjiao Zuo, Ruihu Zhao, Rong Huang, Yingwei Xue and Hongjiang Song
Cancers 2023, 15(9), 2531; https://doi.org/10.3390/cancers15092531 - 28 Apr 2023
Cited by 3 | Viewed by 1302
Abstract
(1) Background: The aim of this study was to explore the predictive ability of lymphocyte subsets for the prognosis of gastric cancer patients who underwent surgery and the prognostic value of CD19 (+) B cell combined with the Prognostic Nutritional Index (PNI). (2) [...] Read more.
(1) Background: The aim of this study was to explore the predictive ability of lymphocyte subsets for the prognosis of gastric cancer patients who underwent surgery and the prognostic value of CD19 (+) B cell combined with the Prognostic Nutritional Index (PNI). (2) Methods: This study involved 291 patients with gastric cancer who underwent surgery at our institution between January 2016 and December 2017. All patients had complete clinical data and peripheral lymphocyte subsets. Differences in clinical and pathological characteristics were examined using the Chi-square test or independent sample t-tests. The difference in survival was evaluated using Kaplan–Meier survival curves and the Log-rank test. Cox’s regression analysis was performed to identify independent prognostic indicators, and nomograms were used to predict survival probabilities. (3) Results: Patients were categorized into three groups based on their CD19 (+) B cell and PNI levels, with 56 cases in group one, 190 cases in group two, and 45 cases in group three. Patients in group one had a shorter progression-free survival (PFS) (HR = 0.444, p < 0.001) and overall survival (OS) (HR = 0.435, p < 0.001). CD19 (+) B cell–PNI had the highest area under the curve (AUC) compared with other indicators, and it was also identified as an independent prognostic factor. Moreover, CD3 (+) T cell, CD3 (+) CD8 (+) T cell, and CD3 (+) CD16 (+) CD56 (+) NK T cell were all negatively correlated with the prognosis, while CD19 (+) B cell was positively associated with the prognosis. The C-index and 95% confidence interval (CI) of nomograms for PFS and OS were 0.772 (0.752–0.833) and 0.773 (0.752–0.835), respectively. (4) Conclusions: Lymphocyte subsets including CD3 (+) T cell, CD3 (+) CD8 (+) T cell, CD3 (+) CD16 (+) CD56 (+) NK T cell, and CD19 (+) B cell were related to the clinical outcomes of patients with gastric cancer who underwent surgery. Additionally, PNI combined with CD19 (+) B cell had higher prognostic value and could be used to identify patients with a high risk of metastasis and recurrence after surgery. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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15 pages, 2506 KiB  
Article
The Membrane Protein Sortilin Is a Potential Biomarker and Target for Glioblastoma
by Mark Marsland, Amiee Dowdell, Sam Faulkner, Craig Gedye, James Lynam, Cassandra P. Griffin, Joanne Marsland, Chen Chen Jiang and Hubert Hondermarck
Cancers 2023, 15(9), 2514; https://doi.org/10.3390/cancers15092514 - 27 Apr 2023
Cited by 4 | Viewed by 1679
Abstract
Glioblastoma (GBM) is a devastating brain cancer with no effective treatment, and there is an urgent need for developing innovative biomarkers as well as therapeutic targets for better management of the disease. The membrane protein sortilin has recently been shown to participate in [...] Read more.
Glioblastoma (GBM) is a devastating brain cancer with no effective treatment, and there is an urgent need for developing innovative biomarkers as well as therapeutic targets for better management of the disease. The membrane protein sortilin has recently been shown to participate in tumor cell invasiveness in several cancers, but its involvement and clinical relevance in GBM is unclear. In the present study, we explored the expression of sortilin and its potential as a clinical biomarker and therapeutic target for GBM. Sortilin expression was investigated by immunohistochemistry and digital quantification in a series of 71 clinical cases of invasive GBM vs. 20 non-invasive gliomas. Sortilin was overexpressed in GBM and, importantly, higher expression levels were associated with worse patient survival, pointing to sortilin tissue expression as a potential prognostic biomarker for GBM. Sortilin was also detectable in the plasma of GBM patients by enzyme-linked immunosorbent assay (ELISA), but no differences were observed between sortilin levels in the blood of GBM vs. glioma patients. In vitro, sortilin was detected in 11 brain-cancer-patient-derived cell lines at the anticipated molecular weight of 100 kDa. Interestingly, targeting sortilin with the orally bioavailable small molecule inhibitor AF38469 resulted in decreased GBM invasiveness, but cancer cell proliferation was not affected, showing that sortilin is targetable in GBM. Together, these data suggest the clinical relevance for sortilin in GBM and support further investigation of GBM as a clinical biomarker and therapeutic target. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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27 pages, 17708 KiB  
Article
Probing the Potential of Defense Response-Associated Genes for Predicting the Progression, Prognosis, and Immune Microenvironment of Osteosarcoma
by Liangkun Huang, Fei Sun, Zilin Liu, Wenyi Jin, Yubiao Zhang, Junwen Chen, Changheng Zhong, Wanting Liang and Hao Peng
Cancers 2023, 15(8), 2405; https://doi.org/10.3390/cancers15082405 - 21 Apr 2023
Cited by 9 | Viewed by 1807
Abstract
Background: The defense response is a type of self-protective response of the body that protects it from damage by pathogenic factors. Although these reactions make important contributions to the occurrence and development of tumors, the role they play in osteosarcoma (OS), particularly in [...] Read more.
Background: The defense response is a type of self-protective response of the body that protects it from damage by pathogenic factors. Although these reactions make important contributions to the occurrence and development of tumors, the role they play in osteosarcoma (OS), particularly in the immune microenvironment, remains unpredictable. Methods: This study included the clinical information and transcriptomic data of 84 osteosarcoma samples and the microarray data of 12 mesenchymal stem cell samples and 84 osteosarcoma samples. We obtained 129 differentially expressed genes related to the defense response (DRGs) by taking the intersection of differentially expressed genes with genes involved in the defense response pathway, and prognostic genes were screened using univariate Cox regression. Least absolute shrinkage and selection operator (LASSO) penalized Cox regression and multivariate Cox regression were then used to establish a DRG prognostic signature (DGPS) via the stepwise method. DGPS performance was examined using independent prognostic analysis, survival curves, and receiver operating characteristic (ROC) curves. In addition, the molecular and immune mechanisms of adverse prognosis in high-risk populations identified by DGPS were elucidated. The results were well verified by experiments. Result: BNIP3, PTGIS, and ZYX were identified as the most important DRGs for OS progression (hazard ratios of 2.044, 1.485, and 0.189, respectively). DGPS demonstrated outstanding performance in the prediction of OS prognosis (area under the curve (AUC) values of 0.842 and 0.787 in the training and test sets, respectively, adj-p < 0.05 in the survival curve). DGPS also performed better than a recent clinical prognostic approach with an AUC value of only 0.674 [metastasis], which was certified in the subsequent experimental results. These three genes regulate several key biological processes, including immune receptor activity and T cell activation, and they also reduce the infiltration of some immune cells, such as B cells, CD8+ T cells, and macrophages. Encouragingly, we found that DGPS was associated with sensitivity to chemotherapeutic drugs including JNK Inhibitor VIII, TGX221, MP470, and SB52334. Finally, we verified the effect of BNIP3 on apoptosis, proliferation, and migration of osteosarcoma cells through experiments. Conclusions: This study elucidated the role and mechanism of BNIP3, PTGIS, and ZYX in OS progression and was well verified by the experimental results, enabling reliable prognostic means and treatment strategies to be proposed for OS patients. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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16 pages, 1977 KiB  
Article
CCR7 Mediates Cell Invasion and Migration in Extrahepatic Cholangiocarcinoma by Inducing Epithelial–Mesenchymal Transition
by Mitsunobu Oba, Yoshitsugu Nakanishi, Tomoko Mitsuhashi, Katsunori Sasaki, Kanako C. Hatanaka, Masako Sasaki, Ayae Nange, Asami Okumura, Mariko Hayashi, Yusuke Yoshida, Takeo Nitta, Takashi Ueno, Toru Yamada, Masato Ono, Shota Kuwabara, Keisuke Okamura, Takahiro Tsuchikawa, Toru Nakamura, Takehiro Noji, Toshimichi Asano, Kimitaka Tanaka, Kiyoshi Takayama, Yutaka Hatanaka and Satoshi Hiranoadd Show full author list remove Hide full author list
Cancers 2023, 15(6), 1878; https://doi.org/10.3390/cancers15061878 - 21 Mar 2023
Cited by 1 | Viewed by 1532
Abstract
The epithelial–mesenchymal transition (EMT) contributes to the metastatic cascade in various tumors. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine (C-C motif) ligand 19 (CCL19), to promote EMT. However, the association between EMT and CCR7 in extrahepatic cholangiocarcinoma (EHCC) remains unknown. [...] Read more.
The epithelial–mesenchymal transition (EMT) contributes to the metastatic cascade in various tumors. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine (C-C motif) ligand 19 (CCL19), to promote EMT. However, the association between EMT and CCR7 in extrahepatic cholangiocarcinoma (EHCC) remains unknown. This study aimed to elucidate the prognostic impact of CCR7 expression and its association with clinicopathological features and EMT in EHCC. The association between CCR7 expression and clinicopathological features and EMT status was examined via the immunohistochemical staining of tumor sections from 181 patients with perihilar cholangiocarcinoma. This association was then investigated in TFK-1 and EGI-1 EHCC cell lines. High-grade CCR7 expression was significantly associated with a large number of tumor buds, low E-cadherin expression, and poor overall survival. TFK-1 showed CCR7 expression, and Western blotting revealed E-cadherin downregulation and vimentin upregulation in response to CCL19 treatment. The wound healing and Transwell invasion assays revealed that the activation of CCR7 by CCL19 enhanced the migration and invasion of TFK-1 cells, which were abrogated by a CCR7 antagonist. These results suggest that a high CCR7 expression is associated with an adverse postoperative prognosis via EMT induction and that CCR7 may be a potential target for adjuvant therapy in EHCC. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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15 pages, 5411 KiB  
Article
The Atypical MAP Kinase MAPK15 Is Required for Lung Adenocarcinoma Metastasis via Its Interaction with NF-κB p50 Subunit and Transcriptional Regulation of Prostaglandin E2 Receptor EP3 Subtype
by Fei-Yuan Yu, Qian Xu, Xiao-Yun Zhao, Hai-Ying Mo, Qiu-Hua Zhong, Li Luo, Andy T. Y. Lau and Yan-Ming Xu
Cancers 2023, 15(5), 1398; https://doi.org/10.3390/cancers15051398 - 22 Feb 2023
Cited by 5 | Viewed by 1558
Abstract
Studying the relatively underexplored atypical MAP Kinase MAPK15 on cancer progression/patient outcomes and its potential transcriptional regulation of downstream genes would be highly valuable for the diagnosis, prognosis, and potential oncotherapy of malignant tumors such as lung adenocarcinoma (LUAD). Here, the expression of [...] Read more.
Studying the relatively underexplored atypical MAP Kinase MAPK15 on cancer progression/patient outcomes and its potential transcriptional regulation of downstream genes would be highly valuable for the diagnosis, prognosis, and potential oncotherapy of malignant tumors such as lung adenocarcinoma (LUAD). Here, the expression of MAPK15 in LUAD was detected by immunohistochemistry and its correlation with clinical parameters such as lymph node metastasis and clinical stage was analyzed. The correlation between the prostaglandin E2 receptor EP3 subtype (EP3) and MAPK15 expression in LUAD tissues was examined, and the transcriptional regulation of EP3 and cell migration by MAPK15 in LUAD cell lines were studied using the luciferase reporter assay, immunoblot analysis, qRT-PCR, and transwell assay. We found that MAPK15 is highly expressed in LUAD with lymph node metastasis. In addition, EP3 is positively correlated with the expression of MAPK15 in LUAD tissues, and we confirmed that MAPK15 transcriptionally regulates the expression of EP3. Upon the knockdown of MAPK15, the expression of EP3 was down-regulated and the cell migration ability was decreased in vitro; similarly, the mesenteric metastasis ability of the MAPK15 knockdown cells was inhibited in in vivo animal experiments. Mechanistically, we demonstrate for the first time that MAPK15 interacts with NF-κB p50 and enters the nucleus, and NF-κB p50 binds to the EP3 promoter and transcriptionally regulates the expression of EP3. Taken together, we show that a novel atypical MAPK and NF-κB subunit interaction promotes LUAD cell migration through transcriptional regulation of EP3, and higher MAPK15 level is associated with lymph node metastasis in patients with LUAD. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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12 pages, 866 KiB  
Article
The Indicative Value of Serum Tumor Markers for Metastasis and Stage of Non-Small Cell Lung Cancer
by Chunyang Jiang, Mengyao Zhao, Shaohui Hou, Xiaoli Hu, Jinchao Huang, Hongci Wang, Changhao Ren, Xiaoying Pan, Ti Zhang, Shengnan Wu, Shun Zhang and Bingsheng Sun
Cancers 2022, 14(20), 5064; https://doi.org/10.3390/cancers14205064 - 16 Oct 2022
Cited by 16 | Viewed by 2779
Abstract
Objective: This study aimed to explore the roles of serum tumor markers for metastasis and stage of non-small cell lung cancer (NSCLC). Methods: This study recruited 3272 NSCLC patients admitted to the Tianjin Union Medical Center and the Tianjin Medical University Cancer Institute [...] Read more.
Objective: This study aimed to explore the roles of serum tumor markers for metastasis and stage of non-small cell lung cancer (NSCLC). Methods: This study recruited 3272 NSCLC patients admitted to the Tianjin Union Medical Center and the Tianjin Medical University Cancer Institute and Hospital. The predictive abilities of some serum tumor markers (carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag), cytokeratin-19 fragment (CYFRA 21-1), neuron-specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP), total prostate-specific antigen (TPSA) and carbohydrate antigen 199 (CA199)) for NSCLC metastasis (intrapulmonary, lymphatic and distant metastasis) and clinical stage were analyzed. Results: Tumor markers exhibited different numerical and proportional distributions in NSCLC patients. Elevated CEA, CYFRA 21-1 and CA199 levels were indicative of tumor metastasis and stage. Increased CEA and CA199 provided an accurate prediction of intrapulmonary and distant metastasis with the area under the receiver operator characteristic curve (AUC) of 0.69 both (p < 0.001); Increased CEA, CYFRA 21-1 and CA199 provided an accurate prediction of lymphatic metastasis with the AUC of 0.62 (p < 0.001). Conclusion: Combined detection of serum tumor markers can indicate tumor metastasis and stage in NSCLC patients. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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20 pages, 3971 KiB  
Article
SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression
by Estefania Carrasco-Garcia, Lidia Lopez, Veronica Moncho-Amor, Fernando Carazo, Paula Aldaz, Manuel Collado, Donald Bell, Ayman Gaafar, Eva Karamitopoulou, Alexandar Tzankov, Manuel Hidalgo, Ángel Rubio, Manuel Serrano, Charles H. Lawrie, Robin Lovell-Badge and Ander Matheu
Cancers 2022, 14(4), 916; https://doi.org/10.3390/cancers14040916 - 12 Feb 2022
Cited by 7 | Viewed by 3021
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer. Methods: We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies. Results: Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression. Conclusions: Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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Review

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13 pages, 1039 KiB  
Review
Benefits from Adjuvant Chemotherapy in Patients with Resected Non-Small Cell Lung Cancer: Possibility of Stratification by Gene Amplification of ACTN4 According to Evaluation of Metastatic Ability
by Takehiro Tozuka, Rintaro Noro, Masahiro Seike and Kazufumi Honda
Cancers 2022, 14(18), 4363; https://doi.org/10.3390/cancers14184363 - 7 Sep 2022
Cited by 2 | Viewed by 2119
Abstract
Surgical treatment is the best curative treatment option for patients with non-small cell lung cancer (NSCLC), but some patients have recurrence beyond the surgical margin even after receiving curative surgery. Therefore, therapies with anti-cancer agents also play an important role perioperatively. In this [...] Read more.
Surgical treatment is the best curative treatment option for patients with non-small cell lung cancer (NSCLC), but some patients have recurrence beyond the surgical margin even after receiving curative surgery. Therefore, therapies with anti-cancer agents also play an important role perioperatively. In this paper, we review the current status of adjuvant chemotherapy in NSCLC and describe promising perioperative therapies, including molecularly targeted therapies and immune checkpoint inhibitors. Previously reported biomarkers of adjuvant chemotherapy for NSCLC are discussed along with their limitations. Adjuvant chemotherapy after resective surgery was most effective in patients with metastatic lesions located just outside the surgical margin; in addition, these metastatic lesions were the most sensitive to adjuvant chemotherapy. Thus, the first step in predicting patients who have sensitivity to adjuvant therapies is to perform a qualified evaluation of metastatic ability using markers such as actinin-4 (ACTN4). In this review, we discuss the potential use of biomarkers in patient stratification for effective adjuvant chemotherapy and, in particular, the use of ACTN4 as a possible biomarker for NSCLC. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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16 pages, 1470 KiB  
Review
A Disintegrin and Metalloproteinase (ADAM) Family—Novel Biomarkers of Selected Gastrointestinal (GI) Malignancies?
by Marta Łukaszewicz-Zając, Sara Pączek and Barbara Mroczko
Cancers 2022, 14(9), 2307; https://doi.org/10.3390/cancers14092307 - 6 May 2022
Cited by 7 | Viewed by 2228
Abstract
The global burden of gastrointestinal (GI) cancers is expected to increase. Therefore, it is vital that novel biomarkers useful for the early diagnosis of these malignancies are established. A growing body of data has linked secretion of proteolytic enzymes, such as metalloproteinases (MMPs), [...] Read more.
The global burden of gastrointestinal (GI) cancers is expected to increase. Therefore, it is vital that novel biomarkers useful for the early diagnosis of these malignancies are established. A growing body of data has linked secretion of proteolytic enzymes, such as metalloproteinases (MMPs), which destroy the extracellular matrix, to pathogenesis of GI tumours. A disintegrin and metalloproteinase (ADAM) proteins belong to the MMP family but have been proven to be unique due to both proteolytic and adhesive properties. Recent investigations have demonstrated that the expression of several ADAMs is upregulated in GI cancer cells. Thus, the objective of this review is to present current findings concerning the role of ADAMs in the pathogenesis of GI cancers, particularly their involvement in the development and progression of colorectal, pancreatic and gastric cancer. Furthermore, the prognostic significance of selected ADAMs in patients with GI tumours is also presented. It has been proven that ADAM8, 9, 10, 12, 15, 17 and 28 might stimulate the proliferation and invasion of GI malignancies and may be associated with unfavourable survival. In conclusion, this review confirms the role of selected ADAMs in the pathogenesis of the most common GI cancers and indicates their promising significance as potential prognostic biomarkers as well as therapeutic targets for GI malignancies. However, due to their non-specific nature, future research on ADAM biology should be performed to elucidate new strategies for the diagnosis of these common and deadly malignancies and treatment of patients with these diseases. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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18 pages, 1289 KiB  
Review
The Entanglement between Mitochondrial DNA and Tumor Metastasis
by Qiwei Wu, Hsiang-i Tsai, Haitao Zhu and Dongqing Wang
Cancers 2022, 14(8), 1862; https://doi.org/10.3390/cancers14081862 - 7 Apr 2022
Cited by 4 | Viewed by 2549
Abstract
Mitochondrial DNA, the genetic material in mitochondria, encodes essential oxidative phosphorylation proteins and plays an important role in mitochondrial respiration and energy transfer. With the development of genome sequencing and the emergence of novel in vivo modeling techniques, the role of mtDNA in [...] Read more.
Mitochondrial DNA, the genetic material in mitochondria, encodes essential oxidative phosphorylation proteins and plays an important role in mitochondrial respiration and energy transfer. With the development of genome sequencing and the emergence of novel in vivo modeling techniques, the role of mtDNA in cancer biology is gaining more attention. Abnormalities of mtDNA result in not only mitochondrial dysfunction of the the cancer cells and malignant behaviors, but regulation of the tumor microenvironment, which becomes more aggressive. Here, we review the recent progress in the regulation of cancer metastasis using mtDNA and the underlying mechanisms, which may identify opportunities for finding novel cancer prediction and therapeutic targets. Full article
(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)
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