Editorial

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Open AccessEditorial

Colorectal Cancer Research: Basic, Preclinical, and Clinical Approaches

by Jean-François Beaulieu

Cancers 2020, 12(2), 416; https://doi.org/10.3390/cancers12020416 - 11 Feb 2020

Cited by 1 | Viewed by 1882

Abstract

Colorectal cancer remains one of the deadliest cancers worldwide [...] Full article

(This article belongs to the Special Issue Colorectal Cancers)

Research

Jump to: Editorial, Review

18 pages, 1310 KiB

Open AccessArticle

Integrated Biobanking and Tumor Model Establishment of Human Colorectal Carcinoma Provides Excellent Tools for Preclinical Research

by Christina S. Mullins, Bianca Micheel, Stephanie Matschos, Matthias Leuchter, Florian Bürtin, Mathias Krohn, Maja Hühns, Ernst Klar, Friedrich Prall and Michael Linnebacher

Cancers 2019, 11(10), 1520; https://doi.org/10.3390/cancers11101520 - 09 Oct 2019

Cited by 30 | Viewed by 3112

Abstract

Over the time period from 2006 to 2017, consecutive patients operated on at the University Medical Center Rostock participated in the comprehensive biobanking and tumor-modelling approach known as the HROC collection. Samples were collected using strict standard operating procedures including blood (serum and [...] Read more.

Over the time period from 2006 to 2017, consecutive patients operated on at the University Medical Center Rostock participated in the comprehensive biobanking and tumor-modelling approach known as the HROC collection. Samples were collected using strict standard operating procedures including blood (serum and lymphocytes), tumor tissue (vital and snap frozen), and adjacent normal epithelium. Patient and tumor data including classification, molecular type, clinical outcome, and results of the model establishment are the essential pillars. Overall, 149 patient-derived xenografts with 34 primary and 35 secondary cell lines were successfully established and encompass all colorectal carcinoma anatomic sites, grading and staging types, and molecular classes. The HROC collection represents one of the largest model assortments from consecutive clinical colorectal carcinoma (CRC) cases worldwide. Statistical analysis identified a variety of clinicopathological and molecular factors associated with model success in univariate analysis. Several of them not identified before include localization, mutational status of K-Ras and B-Raf, MSI-status, and grading and staging parameters. In a multivariate analysis model, success solely correlated positively with the nodal status N1 and mutations in the genes K-Ras and B-Raf. These results imply that generating CRC tumor models on the individual patient level is worth considering especially for advanced tumor cases with a dismal prognosis. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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20 pages, 6994 KiB

Open AccessArticle

Maintenance BEZ235 Treatment Prolongs the Therapeutic Effect of the Combination of BEZ235 and Radiotherapy for Colorectal Cancer

by Yu-Hsuan Chen, Chun-Wei Wang, Ming-Feng Wei, Yi-Shin Tzeng, Keng-Hsueh Lan, Ann-Lii Cheng and Sung-Hsin Kuo

Cancers 2019, 11(8), 1204; https://doi.org/10.3390/cancers11081204 - 19 Aug 2019

Cited by 10 | Viewed by 3169

Abstract

Our previous study demonstrated that administration of NVP-BEZ235 (BEZ235), a dual PI3K/mTOR inhibitor, before radiotherapy (RT) enhanced the radiotherapeutic effect in colorectal cancer (CRC) cells both in vitro and in vivo. Here, we evaluated whether maintenance BEZ235 treatment, after combinatorial BEZ235 + RT [...] Read more.

Our previous study demonstrated that administration of NVP-BEZ235 (BEZ235), a dual PI3K/mTOR inhibitor, before radiotherapy (RT) enhanced the radiotherapeutic effect in colorectal cancer (CRC) cells both in vitro and in vivo. Here, we evaluated whether maintenance BEZ235 treatment, after combinatorial BEZ235 + RT therapy, prolonged the antitumor effect in CRC. K-RAS mutant CRC cells (HCT116 and SW480), wild-type CRC cells (HT29), and HCT116 xenograft tumors were separated into the following six study groups: (1) untreated (control); (2) RT alone; (3) BEZ235 alone; (4) RT + BEZ235; (5) maintenance BEZ235 following RT + BEZ235 (RT + BEZ235 + mBEZ235); and (6) maintenance BEZ235 following BEZ235 (BEZ235 + mBEZ235). RT + BEZ235 + mBEZ235 treatment significantly inhibited cell viability and increased apoptosis in three CRC cell lines compared to the other five treatments in vitro. In the HCT116 xenograft tumor model, RT + BEZ235 + mBEZ235 treatment significantly reduced the tumor size when compared to the other five treatments. Furthermore, the expression of mTOR signaling molecules (p-rpS6 and p-eIF4E), DNA double-strand break (DSB) repair-related molecules (p-ATM and p-DNA-PKcs), and angiogenesis-related molecules (VEGF-A and HIF-1α) was significantly downregulated after RT + BEZ235 + mBEZ235 treatment both in vitro and in vivo when compared to the RT + BEZ235, RT, BEZ235, BEZ235 + mBEZ235, and control treatments. Cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), 53BP1, and γ-H2AX expression in the HCT116 xenograft tissue and three CRC cell lines were significantly upregulated after RT + BEZ235 + mBEZ235 treatment. Maintenance BEZ235 treatment in CRC cells prolonged the inhibition of cell viability, enhancement of apoptosis, attenuation of mTOR signaling, impairment of the DNA-DSB repair mechanism, and downregulation of angiogenesis that occurred due to concurrent BEZ235 and RT treatment. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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14 pages, 3031 KiB

Open AccessArticle

Hepatic Resection Following Selective Internal Radiation Therapy for Colorectal Cancer Metastases in the FOXFIRE Clinical Trial: Clinical Outcomes and Distribution of Microspheres

by Helen Winter, Joseph Rassam, Pradeep S. Virdee, Rob Goldin, Priyankaa Pitcheshwar, Klara Weaver, John Primrose, David P. Berry, Harpreet S. Wasan and Ricky A. Sharma

Cancers 2019, 11(8), 1155; https://doi.org/10.3390/cancers11081155 - 12 Aug 2019

Cited by 11 | Viewed by 3971

Abstract

The FOXFIRE (5-Fluorouracil, OXaliplatin and Folinic acid ± Interventional Radio-Embolisation) clinical trial combined systemic chemotherapy (OxMdG: Oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radio-embolisation) using yttrium-90 resin microspheres in the first-line management for liver-dominant metastatic colorectal cancer (CRC). [...] Read more.

The FOXFIRE (5-Fluorouracil, OXaliplatin and Folinic acid ± Interventional Radio-Embolisation) clinical trial combined systemic chemotherapy (OxMdG: Oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radio-embolisation) using yttrium-90 resin microspheres in the first-line management for liver-dominant metastatic colorectal cancer (CRC). We report clinical outcomes for patients having hepatic resection after this novel combination therapy and an exploratory analysis of histopathology. Multi-Disciplinary Teams deemed all patients inoperable before trial registration and reassessed them during protocol therapy. Proportions were compared using Chi-squared tests and survival using Cox models. FOXFIRE randomised 182 participants to chemotherapy alone and 182 to chemotherapy with SIRT. There was no statistically significant difference in the resection rate between groups: Chemotherapy alone was 18%, (n = 33); SIRT combination was 21% (n = 38) (p = 0.508). There was no statistically significant difference between groups in the rate of liver surgery, nor in survival from time of resection (hazard ratio (HR) = 1.55; 95% confidence interval (CI) = 0.83–2.89). In the subgroup studied for histopathology, microsphere density was highest at the tumour periphery. Patients treated with SIRT plus chemotherapy displayed lower values of viable tumour in comparison to those treated with chemotherapy alone (p < 0.05). This study promotes the feasibility of hepatic resection following SIRT. Resin microspheres appear to preferentially distribute at the tumour periphery and may enhance tumour regression. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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15 pages, 5951 KiB

Open AccessArticle

Flavopereirine Suppresses the Growth of Colorectal Cancer Cells through P53 Signaling Dependence

by Jhy-Ming Li, Yun-Ching Huang, Yi-Hung Kuo, Chih-Chung Cheng, Feng-Che Kuan, Shun-Fu Chang, Ying-Ray Lee, Chih-Chien Chin and Chung-Sheng Shi

Cancers 2019, 11(7), 1034; https://doi.org/10.3390/cancers11071034 - 22 Jul 2019

Cited by 13 | Viewed by 4274

Abstract

Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. The outcome of CRC patients remains poor. Thus, a new strategy for CRC treatment is urgently needed. Flavopereirine is a β-carboline alkaloid extracted from Geissospermum vellosii, which can reduce the [...] Read more.

Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. The outcome of CRC patients remains poor. Thus, a new strategy for CRC treatment is urgently needed. Flavopereirine is a β-carboline alkaloid extracted from Geissospermum vellosii, which can reduce the viability of various cancer cells through an unknown mode of action. The aim of the present study was to investigate the functional mechanism and therapeutic potential of flavopereirine on CRC cells in vitro and in vivo. Our data showed that flavopereirine significantly lowered cellular viability, caused intrinsic and extrinsic apoptosis, and induced G2/M-phase cell cycle arrest in CRC cells. Flavopereirine downregulated Janus kinases-signal transducers and activators of transcription (JAKs-STATs) and cellular myelocytomatosis (c-Myc) signaling in CRC cells. In contrast, the enforced expressions of constitutive active STAT3 and c-Myc could not restore flavopereirine-induced viability reduction. Moreover, flavopereirine enhanced P53 expression and phosphorylation in CRC cells. CRC cells with P53 knockout or loss-of-function mutation significantly diminished flavopereirine-mediated viability reduction, indicating that P53 activity plays a major role in flavopereirine-mediated CRC cell growth suppression. Flavopereirine also significantly repressed CRC cell xenograft growth in vivo by upregulating P53 and P21 and inducing apoptosis. In conclusion, flavopereirine-mediated growth suppression in CRC cells depended on the P53-P21, but not the JAKs-STATs-c-Myc signaling pathway. The present study suggests that flavopereirine may be efficacious in the clinical treatment of CRC harboring functional P53 signaling. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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17 pages, 2654 KiB

Open AccessArticle

Genetic Aberration Analysis in Thai Colorectal Adenoma and Early-Stage Adenocarcinoma Patients by Whole-Exome Sequencing

by Thoranin Intarajak, Wandee Udomchaiprasertkul, Chakrit Bunyoo, Jutamas Yimnoon, Kamonwan Soonklang, Kriangpol Wiriyaukaradecha, Wisut Lamlertthon, Thaniya Sricharunrat, Worawit Chaiwiriyawong, Bunchorn Siriphongpreeda, Sawannee Sutheeworapong, Kanthida Kusonmano, Weerayuth Kittichotirat, Chinae Thammarongtham, Piroon Jenjaroenpun, Thidathip Wongsurawat, Intawat Nookaew, Chirayu Auewarakul and Supapon Cheevadhanarak

Cancers 2019, 11(7), 977; https://doi.org/10.3390/cancers11070977 - 12 Jul 2019

Cited by 10 | Viewed by 5087

Abstract

Colorectal adenomas are precursor lesions of colorectal adenocarcinoma. The transition from adenoma to carcinoma in patients with colorectal cancer (CRC) has been associated with an accumulation of genetic aberrations. However, criteria that can screen adenoma progression to adenocarcinoma are still lacking. This present [...] Read more.

Colorectal adenomas are precursor lesions of colorectal adenocarcinoma. The transition from adenoma to carcinoma in patients with colorectal cancer (CRC) has been associated with an accumulation of genetic aberrations. However, criteria that can screen adenoma progression to adenocarcinoma are still lacking. This present study is the first attempt to identify genetic aberrations, such as the somatic mutations, copy number variations (CNVs), and high-frequency mutated genes, found in Thai patients. In this study, we identified the genomic abnormality of two sample groups. In the first group, five cases matched normal-colorectal adenoma-colorectal adenocarcinoma. In the second group, six cases matched normal-colorectal adenomas. For both groups, whole-exome sequencing was performed. We compared the genetic aberration of the two sample groups. In both normal tissues compared with colorectal adenoma and colorectal adenocarcinoma analyses, somatic mutations were observed in the tumor suppressor gene APC (Adenomatous polyposis coli) in eight out of ten patients. In the group of normal tissue comparison with colorectal adenoma tissue, somatic mutations were also detected in Catenin Beta 1 (CTNNB1), Family With Sequence Similarity 123B (FAM123B), F-Box And WD Repeat Domain Containing 7 (FBXW7), Sex-Determining Region Y-Box 9 (SOX9), Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5), Frizzled Class Receptor 10 (FZD10), and AT-Rich Interaction Domain 1A (ARID1A) genes, which are involved in the Wingless-related integration site (Wnt) signaling pathway. In the normal tissue comparison with colorectal adenocarcinoma tissue, Kirsten retrovirus-associated DNA sequences (KRAS), Tumor Protein 53 (TP53), and Ataxia-Telangiectasia Mutated (ATM) genes are found in the receptor tyrosine kinase-RAS (RTK–RAS) signaling pathway and p53 signaling pathway, respectively. These results suggest that APC and TP53 may act as a potential screening marker for colorectal adenoma and early-stage CRC. This preliminary study may help identify patients with adenoma and early-stage CRC and may aid in establishing prevention and surveillance strategies to reduce the incidence of CRC. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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18 pages, 4409 KiB

Open AccessArticle

Synergy between Auranofin and Celecoxib against Colon Cancer In Vitro and In Vivo through a Novel Redox-Mediated Mechanism

by Yi Han, Ping Chen, Yanyu Zhang, Wenhua Lu, Wenwen Ding, Yao Luo, Shijun Wen, Ruihua Xu, Panpan Liu and Peng Huang

Cancers 2019, 11(7), 931; https://doi.org/10.3390/cancers11070931 - 03 Jul 2019

Cited by 39 | Viewed by 5006

Abstract

Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity in various experimental models. Its clinical applications in cancer treatment, however, have been hampered due in part to its relatively [...] Read more.

Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity in various experimental models. Its clinical applications in cancer treatment, however, have been hampered due in part to its relatively moderate activity as a single agent. In this study, we performed a high-throughput screening of the FDA-approved drug library for clinical compounds that potentiate the anticancer activity auranofin, and unexpectedly identified an anti-inflammatory drug celecoxib (CE) that potently enhanced the therapeutic activity of AF in vitro and in vivo. Mechanistically, AF/CE combination induced severe oxidative stress that caused ROS-mediated inhibition of hexokinase (HK) and a disturbance of mitochondrial redox homeostasis, resulting in a significant decrease of ATP generation. The CE-induced ROS increase together with AF-medicated inhibition of thioredoxin reductase cause a shift of Trx2 to an oxidized state, leading to degradation of MTCO2 and dysfunction of the electron transport chain. Our study has identified a novel drug combination that effectively eliminates cancer cells in vivo. Since AF and CE are FDA-approved drugs that are currently used in the clinic, it is feasible to translate the findings of this study into clinical applications for cancer treatment. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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19 pages, 2310 KiB

Open AccessArticle

Wnt-11 as a Potential Prognostic Biomarker and Therapeutic Target in Colorectal Cancer

by Irantzu Gorroño-Etxebarria, Urko Aguirre, Saray Sanchez, Nerea González, Antonio Escobar, Ignacio Zabalza, José Maria Quintana, Maria dM Vivanco, Jonathan Waxman and Robert M. Kypta

Cancers 2019, 11(7), 908; https://doi.org/10.3390/cancers11070908 - 28 Jun 2019

Cited by 18 | Viewed by 3866

Abstract

The expression of the secreted factor Wnt-11 is elevated in several types of cancer, including colorectal cancer, where it promotes cancer cell migration and invasion. Analysis of colorectal cancer gene expression databases associated WNT11 mRNA expression with increased likelihood of metastasis in a [...] Read more.

The expression of the secreted factor Wnt-11 is elevated in several types of cancer, including colorectal cancer, where it promotes cancer cell migration and invasion. Analysis of colorectal cancer gene expression databases associated WNT11 mRNA expression with increased likelihood of metastasis in a subset of patients. WNT11 expression was correlated with the expression of the Wnt receptors FZD6, RYK, and PTK7, and the combined expression of WNT11, FZD6 and RYK or PTK7 was associated with an increased risk of 5-year mortality rates. Immunohistochemical analysis of Wnt-11 in a cohort of 357 colorectal cancer patients found significantly higher Wnt-11 levels in tumors, compared with benign tissue. Elevated Wnt-11 levels occurred more frequently in rectal tumors than in colonic tumors and in tumors from women than men. In univariate analysis, increased Wnt-11 expression was also associated with tumor invasion and increased 5-year mortality. High Wnt-11 levels were not associated with high levels of nuclear β-catenin, suggesting Wnt-11 is not simply an indicator for activation of β-catenin-dependent signaling. Expression of Wnt-11 in colorectal cancer cell lines expressing low endogenous Wnt-11 inhibited β-catenin/Tcf activity and increased ATF2-dependent transcriptional activity. WNT11 gene silencing and antibody-mediated inhibition of Wnt-11 in colorectal cancer cell lines expressing high Wnt-11 reduced their capacity for invasion. Together, these observations suggest that Wnt-11 could be a potential target for the treatment of patients with invasive colorectal cancer. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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18 pages, 5208 KiB

Open AccessArticle

Heightened JNK Activation and Reduced XIAP Levels Promote TRAIL and Sunitinib-Mediated Apoptosis in Colon Cancer Models

by Devalingam Mahalingam, Jennifer S. Carew, Claudia M. Espitia, Robbert H. Cool, Francis J. Giles, Steven de Jong and Steffan T. Nawrocki

Cancers 2019, 11(7), 895; https://doi.org/10.3390/cancers11070895 - 26 Jun 2019

Cited by 12 | Viewed by 3342

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis that may be a promising agent in cancer therapy due to its selectivity toward tumor cells. However, many cancer cells are resistant to TRAIL due to defects in apoptosis signaling or [...] Read more.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis that may be a promising agent in cancer therapy due to its selectivity toward tumor cells. However, many cancer cells are resistant to TRAIL due to defects in apoptosis signaling or activation of survival pathways. We hypothesized that a disruption of pro-survival signaling cascades with the multi-tyrosine kinase inhibitor sunitinib would be an effective strategy to enhance TRAIL-mediated apoptosis. Here we demonstrate that sunitinib significantly augments the anticancer activity of TRAIL in models of colon cancer. The therapeutic benefit of the TRAIL/sunitinib combination was associated with increased apoptosis marked by enhanced caspase-3 cleavage and DNA fragmentation. Overexpression of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2) in HCT116 cells reduced TRAIL/sunitinib-mediated apoptosis, further supporting that sunitinib enhances the anticancer activity of TRAIL via augmented apoptosis. Analysis of pro-survival factors identified that the combination of TRAIL and sunitinib significantly downregulated the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP) through a c-Jun N-terminal kinase (JNK)-mediated mechanism. Short hairpin RNA (shRNA)-mediated knockdown of JNK confirmed its key role in the regulation of sensitivity to this combination as cells with suppressed JNK expression exhibited significantly reduced TRAIL/sunitinib-mediated apoptosis. Importantly, the therapeutic benefit of the TRAIL/sunitinib combination was validated in the HCT116-Luc and HCT15 colon cancer xenograft models, which both demonstrated significant anti-tumor activity in response to combination treatment. Collectively, our data demonstrate that sunitinib enhances TRAIL-mediated apoptosis by heightened JNK activation, diminished XIAP levels, and augmented apoptosis. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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18 pages, 2357 KiB

Open AccessArticle

(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma—Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis

by Maider Beitia, Jon Danel Solano-Iturri, Peio Errarte, Julio Calvete-Candenas, Alberto Loizate, Mari Carmen Etxezarraga, Begoña Sanz and Gorka Larrinaga

Cancers 2019, 11(6), 881; https://doi.org/10.3390/cancers11060881 - 24 Jun 2019

Cited by 12 | Viewed by 3717

Abstract

(Pro)renin receptor (PRR) is a protein that takes part in several signaling pathways such as Renin Angiotensin System and Wnt signalling. Its biological role has recently been related to cancer progression and in this study, we investigated its relevance in colorectal cancer (CRC). [...] Read more.

(Pro)renin receptor (PRR) is a protein that takes part in several signaling pathways such as Renin Angiotensin System and Wnt signalling. Its biological role has recently been related to cancer progression and in this study, we investigated its relevance in colorectal cancer (CRC). To that end, we analysed the immunohistochemical expression of PRR in adenomatous polyps and CRCs from the same patients (n = 42), and in primary tumours and nodal and liver metastases from advanced CRC patients (n = 294). In addition, the soluble fraction of PRR was measured by ELISA in plasma samples from 161 CRC patients. The results showed that PRR expression was gradually augmented along the uninvolved mucosa–adenoma–adenocarcinoma sequence. Besides, the stronger expression of PRR in primary tumours was markedly associated with local tumour extent and the onset of metastases. Moreover, PRR expression in both primary and distant metastases was associated with worse 5- and 10-year survival of CRC patients. Plasmatic PRR levels did not change with respect to controls and were not associated with CRC aggressiveness. These results suggest a key role of PRR in the development and progression of CRC and a potential use of this protein as a new prognostic biomarker and/or therapeutic target for this disease. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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9 pages, 768 KiB

Open AccessArticle

Human Colorectal Carcinoma Infiltrating B Lymphocytes Are Active Secretors of the Immunoglobulin Isotypes A, G, and M

by Christina Susanne Mullins, Michael Gock, Mathias Krohn and Michael Linnebacher

Cancers 2019, 11(6), 776; https://doi.org/10.3390/cancers11060776 - 04 Jun 2019

Cited by 9 | Viewed by 3204

Abstract

Despite the importance of tumor infiltrating B cells (TiBc) in immunological circuits, their functional role is scarcely investigated. Here, we analyzed immunoglobulin (Ig) secretion of the subtypes IgA, IgG, and IgM of TiBc from freshly resected primary and secondary colorectal carcinomas (CRC) by [...] Read more.

Despite the importance of tumor infiltrating B cells (TiBc) in immunological circuits, their functional role is scarcely investigated. Here, we analyzed immunoglobulin (Ig) secretion of the subtypes IgA, IgG, and IgM of TiBc from freshly resected primary and secondary colorectal carcinomas (CRC) by FluoroSpot (n = 30 CRC) directly ex vivo. High, intermediate, and low secretion was observed in 33%, 37%, and 30% of the tumors for IgA; in 10%, 27%, and 63% for IgG; and in 21%, 36%, and 50% for IgM, respectively. These ex vivo data validate our previous findings: Most TiBc present in the CRC microenvironment are functional since they produce and actively secrete Ig (IgA > IgG > IgM). Of note, the presence of major histocompatibility complex (MHC) class II expressing cells in the tumor micromilieu only correlated with IgG secretion (p = 0.0004). Supporting recent findings in several other tumor entities, TiBc in CRC thus likely can contribute to tumor control in a dual role of sole antigen-presentation and additionally anti-tumoral Ig-production. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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13 pages, 3281 KiB

Open AccessArticle

miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis

by Kwang Seock Kim, Dongjun Jeong, Ita Novita Sari, Yoseph Toni Wijaya, Nayoung Jun, Sanghyun Lee, Ying-Gui Yang, Sae Hwan Lee and Hyog Young Kwon

Cancers 2019, 11(5), 735; https://doi.org/10.3390/cancers11050735 - 27 May 2019

Cited by 5 | Viewed by 3279

Abstract

Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b [...] Read more.

Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b was significantly downregulated in both patient-derived CRC tissues and CRC cell lines compared to normal tissues and non-cancer cell lines. Also, miR551b significantly inhibited the motility of CRC cells in vitro, including migration, invasion, and wound healing rates, but did not affect cell proliferation. Mechanistically, miR551b targets and inhibits the expression of ZEB1 (Zinc finger E-box-binding homeobox 1), resulting in the dysregulation of EMT (epithelial-mesenchymal transition) signatures. More importantly, miR551b overexpression was found to reduce the tumor size in a xenograft model of CRC cells in vivo. Furthermore, bioinformatic analyses showed that miR551b expression levels were markedly downregulated in the advanced-stage CRC tissues compared to normal tissues, and ZEB1 was associated with the disease progression in CRC patients. Our findings indicated that miR551b could serve as a potential diagnostic biomarker and could be utilized to improve the therapeutic outcomes of CRC patients. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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17 pages, 2189 KiB

Open AccessArticle

Effects of Copper Chelation on BRAF^V600E Positive Colon Carcinoma Cells

by Silvia Baldari, Giuliana Di Rocco, Marie C. Heffern, Timothy A. Su, Christopher J. Chang and Gabriele Toietta

Cancers 2019, 11(5), 659; https://doi.org/10.3390/cancers11050659 - 12 May 2019

Cited by 36 | Viewed by 6934

Abstract

High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role [...] Read more.

High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAF^V600E). Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson’s disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAF^V600E mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAF^V600E mutation compared to BRAF^wt acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAF^V600E cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAF^V600E mutation. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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17 pages, 3299 KiB

Open AccessArticle

Quantitative Proteomics Identifies DNA Repair as a Novel Biological Function for Hepatocyte Nuclear Factor 4α in Colorectal Cancer Cells

by Jean-Philippe Babeu, Samuel D. Wilson, Élie Lambert, Dominique Lévesque, François-Michel Boisvert and François Boudreau

Cancers 2019, 11(5), 626; https://doi.org/10.3390/cancers11050626 - 05 May 2019

Cited by 11 | Viewed by 4216

Abstract

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that acts as a master regulator of genes for several endoderm-derived tissues, including the intestine, in which it plays a central role during development and tumorigenesis. To better define the mechanisms by which HNF4α [...] Read more.

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that acts as a master regulator of genes for several endoderm-derived tissues, including the intestine, in which it plays a central role during development and tumorigenesis. To better define the mechanisms by which HNF4α can influence these processes, we identified proteins interacting with HNF4α using stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomics with either immunoprecipitation of green fluorescent protein (GFP) or with proximity-dependent purification by the biotin ligase BirA (BioID), both fused to HNF4α. Surprisingly, these analyses identified a significant enrichment of proteins characterized with a role in DNA repair, a so far unidentified biological feature of this transcription factor. Several of these proteins including PARP1, RAD50, and DNA-PKcs were confirmed to interact with HNF4α in colorectal cancer cell lines. Following DNA damage, HNF4α was able to increase cell viability in colorectal cancer cells. Overall, these observations identify a potential role for this transcription factor during the DNA damage response. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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9 pages, 532 KiB

Open AccessArticle

Oxaliplatin-Based Chemotherapy in Patients with Metastatic Colorectal Cancer Aged at Least 75 Years: A Post-Hoc Subgroup Analysis of Three Phase II Trials

by Gerardo Rosati, Stefano Cordio, Giorgio Reggiardo, Giuseppe Aprile, Alfredo Butera, Antonio Avallone, Aniello Tucci, Giuseppe Novello, Giuseppina Blanco, Giuseppe Caputo, Domenico Bilancia and Roberto Bordonaro

Cancers 2019, 11(4), 578; https://doi.org/10.3390/cancers11040578 - 24 Apr 2019

Cited by 4 | Viewed by 2939

Abstract

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer studies based on a combination chemotherapy containing oxaliplatin. Our group conducted three phase II trials in elderly patients in recent years. A post-hoc subgroup analysis of 67 patients aged [...] Read more.

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer studies based on a combination chemotherapy containing oxaliplatin. Our group conducted three phase II trials in elderly patients in recent years. A post-hoc subgroup analysis of 67 patients aged at least 75 years was included in this study. Oxaliplatin was combined with capecitabine in two trials and with uracil-tegafur (UFT) plus folinic acid in the third trial. In one study, bevacizumab was also added to chemotherapy. The median age of patients was 77 years, and all had a good performance status (0 to 1). The observed overall response rate was 45%, comparable to younger patients (51%, p = 0.49). The estimated median progression-free survival (PFS) time and overall survival (OS) time were 8.7 and 19.3 months, respectively. These results did not significantly differ from those in younger patients (8.0 months for PFS (p = 0.58) and 19.7 months for OS (p = 0.94), respectively). The most common grade 3–4 adverse events included diarrhea (13%), fatigue (13%), peripheral neuropathy (10%), and neutropenia (7%). Moreover, the toxicity was never statistically different from that in younger patients. The efficacy of oxaliplatin-based combination was maintained in fit elderly patients ≥75 years. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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18 pages, 2374 KiB

Open AccessArticle

Dual Targeting of Y-Box Binding Protein-1 and Akt Inhibits Proliferation and Enhances the Chemosensitivity of Colorectal Cancer Cells

by Eva Maier, Felix Attenberger, Aadhya Tiwari, Konstanze Lettau, Simone Rebholz, Birgit Fehrenbacher, Martin Schaller, Cihan Gani and Mahmoud Toulany

Cancers 2019, 11(4), 562; https://doi.org/10.3390/cancers11040562 - 19 Apr 2019

Cited by 18 | Viewed by 4226

Abstract

KRAS-mutated colorectal cancers (CRCs) are resistant to cetuximab treatment. The multifunctional Y-box binding protein 1 (YB-1) is overexpressed in CRC and is associated with chemoresistance. In this study, the effects of oncogenic mutated KRAS(G12V) and KRAS(G13D) on YB-1 phosphorylation were investigated in CRC [...] Read more.

KRAS-mutated colorectal cancers (CRCs) are resistant to cetuximab treatment. The multifunctional Y-box binding protein 1 (YB-1) is overexpressed in CRC and is associated with chemoresistance. In this study, the effects of oncogenic mutated KRAS(G12V) and KRAS(G13D) on YB-1 phosphorylation were investigated in CRC cells. The effects of the inhibition of p90 ribosomal S6 kinase (RSK) on YB-1 phosphorylation, cell proliferation and survival were tested with and without treatment with 5-fluorouracil using pharmacological inhibitors and siRNA. YB-1 phosphorylation status and subcellular distribution in CRC patient tissues were determined by immunofluorescence staining and confocal microscopy. Endogenous expression of mutated KRAS(G13D) and conditional expression of KRAS(G12V) significantly stimulated YB-1 phosphorylation via RSK and were associated with cetuximab resistance. Inhibition of YB-1 by targeting RSK stimulated the Akt signaling pathway, and this stimulation occurred independently of KRAS mutational status. Akt activation interfered with the antiproliferative effect of the RSK inhibitor. Consequently, dual targeting of RSK and Akt efficiently inhibited cell proliferation in KRAS(G13D)-mutated HCT116 and KRAS wild-type SW48 cells. Treatment with 5-fluorouracil (5-FU) significantly enhanced YB-1 phosphorylation in KRAS(G13D)-mutated HCT116 cells but not in KRAS wild-type SW48 cells. Dual targeting of Akt and RSK sensitized HCT116 cells to 5-FU by stimulating 5-FU-induced apoptosis and inhibiting repair of 5-FU-induced DNA damage. YB-1 was highly phosphorylated in CRC patient tumor tissues and was mainly localized in the nucleus. Together, dual targeting of RSK and Akt may be an alternative molecular targeting approach to cetuximab for treating CRC in which YB-1 is highly phosphorylated. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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15 pages, 4008 KiB

Open AccessArticle

Expression Profiling of Calcium Channels and Calcium-Activated Potassium Channels in Colorectal Cancer

by Sajida Ibrahim, Hassan Dakik, Christophe Vandier, Romain Chautard, Gilles Paintaud, Frédéric Mazurier, Thierry Lecomte, Maxime Guéguinou and William Raoul

Cancers 2019, 11(4), 561; https://doi.org/10.3390/cancers11040561 - 19 Apr 2019

Cited by 51 | Viewed by 5512

Abstract

Background: Colorectal cancer (CRC) is a highly devastating cancer. Ca²⁺-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca²⁺ channels and Ca²⁺-dependent potassium channels [...] Read more.

Background: Colorectal cancer (CRC) is a highly devastating cancer. Ca²⁺-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca²⁺ channels and Ca²⁺-dependent potassium channels (KCa) with CRC using the transcriptional profile of their genes. Methods: We selected a total of 35 genes covering KCa channels KCNN1–4, KCNMA1 and their subunits KCNMB1–4, endoplasmic reticulum (ER) calcium sensors STIM1 and STIM2, Ca²⁺ channels ORAI1–3 and the family of cation channels TRP (TRPC1–7, TRPA1, TRPV1/2,4–6 and TRPM1–8). We analyzed their expression in two public CRC datasets from The Cancer Genome Atlas (TCGA) and GSE39582. Results: KCNN4 and TRPM2 were induced while KCNMA1 and TRPM6 were downregulated in tumor tissues comparing to normal tissues. In proximal tumors, STIM2 and KCNN2 were upregulated while ORAI2 and TRPM6 were downregulated. ORAI1 decreased in lymph node metastatic tumors. TRPC1 and ORAI3 predicted poor prognosis in CRC patients. Moreover, we found that ORAI3/ORAI1 ratio is increased in CRC progression and predicted poor prognosis. Conclusions: KCa and Ca²⁺ channels could be important contributors to CRC initiation and progression. Our results provide new insights on KCa and Ca²⁺ channels remodeling in CRC. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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14 pages, 1596 KiB

Open AccessArticle

Improvement of Metastatic Colorectal Cancer Patient Survival: Single Institution Experience

by Elisabetta Fenocchio, Federica Colombi, Maria Grazia Calella, Roberto Filippi, Ilaria Depetris, Giovanna Chilà, Pasquale Lombardi, Donatella Marino, Celeste Cagnazzo, Renato Ferraris, Marco Vaira, Massimo Aglietta and Francesco Leone

Cancers 2019, 11(3), 369; https://doi.org/10.3390/cancers11030369 - 15 Mar 2019

Cited by 5 | Viewed by 2542

Abstract

The survival rates of patients with metastatic colorectal cancer (mCRC) have improved in recent years. We analysed the survival of mCRC patients followed at a single institution over the last 17 years. We retrospectively collected data from 899 mCRC patients treated from 2001 [...] Read more.

The survival rates of patients with metastatic colorectal cancer (mCRC) have improved in recent years. We analysed the survival of mCRC patients followed at a single institution over the last 17 years. We retrospectively collected data from 899 mCRC patients treated from 2001 to 2016. Patients were divided into two groups based on the year of diagnosis: Cohort A (2001–2006) and Cohort B (2007–2014). A total of 788 patients were analysed. The median survival of the whole population was 32.0 months with a significant difference between Cohort A and B (29.2 vs. 33.5 months; p = 0.041). Surgical procedures significantly increased in Cohort B, however, no significant changes in survival were observed in patients undergoing surgery (58.9 months Cohort A vs. 58.2 months Cohort B, p = 0.822). Similarly, we did not demonstrate survival improvement in patients treated with systemic therapy alone (18.9 months Cohort A vs. 20.7 months Cohort B; p = 0.948). At the multivariate analysis, right-sided primary and synchronous metastatic tumour were found to be independent unfavorable prognostic factors. Improvements of mCRC patient survival might relate to integrated approach, with more patients undergoing extra-hepatic surgery. The medical approach seems to have had a more favourable impact on subgroups characterized by a worse prognosis. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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18 pages, 2138 KiB

Open AccessArticle

Deciphering the Mechanism of Action Involved in Enhanced Suicide Gene Colon Cancer Cell Killer Effect Mediated by Gef and Apoptin

by Blanca Cáceres, Alberto Ramirez, Esmeralda Carrillo, Gema Jimenez, Carmen Griñán-Lisón, Elena López-Ruiz, Yaiza Jiménez-Martínez, Juan A. Marchal and Houria Boulaiz

Cancers 2019, 11(2), 264; https://doi.org/10.3390/cancers11020264 - 23 Feb 2019

Cited by 16 | Viewed by 4165

Abstract

Despite the great advances in cancer treatment, colorectal cancer has emerged as the second highest cause of death from cancer worldwide. For this type of tumor, the use of suicide gene therapy could represent a novel therapy. We recently demonstrated that co-expression of [...] Read more.

Despite the great advances in cancer treatment, colorectal cancer has emerged as the second highest cause of death from cancer worldwide. For this type of tumor, the use of suicide gene therapy could represent a novel therapy. We recently demonstrated that co-expression of gef and apoptin dramatically inhibits proliferation of the DLD-1 colon cell line. In the present manuscript, we try to establish the mechanism underlying the enhanced induction of apoptosis by triggering both gef and apoptin expression in colon tumor cells. Scanning microscopy reveals that simultaneous expression of gef and apoptin induces the apparition of many “pores” in the cytoplasmic membrane not detected in control cell lines. The formation of pores induced by the gef gene and accentuated by apoptin results in cell death by necrosis. Moreover, we observed the presence of apoptotic cells. Performing protein expression analysis using western blot, we revealed an activation of mitochondrial apoptosis (increased expression of Pp53, cytochrome c, Bax, and caspase 9) and also the involvement of the extrinsic pathway through caspase 8activation. In conclusion, in this manuscript we demonstrate for the first time that the extrinsic pathway of apoptosis and pore formation is also involved in the cell death caused by the co-expression of the gef and apoptin genes. Our results suggest that co-expression of gef and apoptin genes induces an increase in post-apoptotic necrotic cell death and could be a valuable tool in the design of new antitumor strategies focused on the enhancement of the immune response against cancer cell death. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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22 pages, 1131 KiB

Open AccessArticle

Progressive Oncological Surgery Is Associated with Increased Curative Resection Rates and Improved Survival in Metastatic Colorectal Cancer

by Florian Primavesi, Stefan Stättner, Tarkan Jäger, Georg Göbel, Jaroslav Presl, Katerina Tomanová, Selina Buchner, Manuel Maglione, Thomas Resch, Jörg Hutter, Dietmar Öfner and Adam Dinnewitzer

Cancers 2019, 11(2), 218; https://doi.org/10.3390/cancers11020218 - 14 Feb 2019

Cited by 11 | Viewed by 3701

Abstract

Background: Secondary resection rates in first-line chemotherapy trials for metastatic colorectal cancer (mCRC) remain below 15%, representing a clear contrast to reports by specialised surgical centres, where progressive liver, peritoneal-surface, and pulmonary surgery increased access to curative-intent treatment. We present a long-term evaluation [...] Read more.

Background: Secondary resection rates in first-line chemotherapy trials for metastatic colorectal cancer (mCRC) remain below 15%, representing a clear contrast to reports by specialised surgical centres, where progressive liver, peritoneal-surface, and pulmonary surgery increased access to curative-intent treatment. We present a long-term evaluation of oncosurgical management in a single-centre, analysing the aggregate effect of gradual implementation of surgical subspecialties and systemic treatments on mCRC patients’ resection rates and prognosis. Methods: Patients with newly diagnosed mCRC from 2003 to 2014 were retrospectively categorised into palliative treatment (PAT) and curative intent surgery (CIS) and three time periods were analysed for treatment changes and factors associated with survival. Results: Four hundred-twenty patients were treated (PAT:250/CIS:170). Over time periods, the number of presenting patients remained consistent, whereas curative resection rates increased from 29% to 55%, facilitated by an increment of patients undergoing hepatectomy (21 to 35%), pulmonary surgery (6 to 17%), and peritonectomy/intraoperative chemotherapy (0 to 8%). Also, recently, significantly more multi-line systemic treatments were applied. The median survival markedly improved from 21.9 months (2003–2006; 95% confidence interval (CI) 17.3–26.5) to 36.5 months (2011–2014; 95% CI 26.6–46.4; p = 0.018). PAT was a significant factor of poor survival and diagnosis of mCRC in the latest time period was independently associated with a distinctly lower risk for palliative treatment (odds ratio 0.15). Conclusions: In modern eras of medical oncology, achieving appropriate resection rates through utilization of state-of-the-art oncological surgery by dedicated experts represents a cornerstone for long-term survival in mCRC. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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Review

Jump to: Editorial, Research

13 pages, 1982 KiB

Open AccessReview

Integrin α6β4 in Colorectal Cancer: Expression, Regulation, Functional Alterations and Use as a Biomarker

by Jean-François Beaulieu

Cancers 2020, 12(1), 41; https://doi.org/10.3390/cancers12010041 - 21 Dec 2019

Cited by 36 | Viewed by 4909

Abstract

Integrin α6β4 is one of the main laminin receptors and is primarily expressed by epithelial cells as an active component of hemidesmosomes. In this article, after a brief summary about integrins in the gut epithelium in general, I review the knowledge and clinical [...] Read more.

Integrin α6β4 is one of the main laminin receptors and is primarily expressed by epithelial cells as an active component of hemidesmosomes. In this article, after a brief summary about integrins in the gut epithelium in general, I review the knowledge and clinical potential of this receptor in human colorectal cancer (CRC) cells. Most CRC cells overexpress both α6 and β4 subunits, in situ in primary tumours as well as in established CRC cell lines. The mechanisms that lead to overexpression have not yet been elucidated but clearly involve specific transcription factors such as MYC. From a functional point of view, one key element affecting CRC cell behaviour is the relocalization of α6β4 to the actin cytoskeleton, favouring a more migratory and anoikis-resistant phenotype. Another major element is its expression under various molecular forms that have the distinct ability to interact with ligands (α6β4 ± ctd) or to promote pro- or anti-proliferative properties (α6Aβ4 vs. α6Bβ4). The integrin α6β4 is thus involved in most steps susceptible to participation with CRC progression. The potential clinical significance of this integrin has begun to be investigated and recent studies have shown that ITGA6 and ITGB4 can be useful biomarkers for CRC early detection in a non-invasive assay and as a prognostic factor, respectively. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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11 pages, 959 KiB

Open AccessReview

How to Deal with Second Line Dilemma in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis

by Antonio Galvano, Lorena Incorvaia, Giuseppe Badalamenti, Sergio Rizzo, Aurelia Guarini, Stefania Cusenza, Luisa Castellana, Nadia Barraco, Valentina Calò, Sofia Cutaia, Giuseppe Currò, Nicola Silvestris, Giordano Domenico Beretta, Viviana Bazan and Antonio Russo

Cancers 2019, 11(8), 1189; https://doi.org/10.3390/cancers11081189 - 15 Aug 2019

Cited by 5 | Viewed by 3311

Abstract

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy with chemotherapy (CT) as second line treatment for metastatic colorectal cancer (mCRC). The right sequence of the treatments in all RAS (KRAS/NRAS) wild type (wt) patients [...] Read more.

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy with chemotherapy (CT) as second line treatment for metastatic colorectal cancer (mCRC). The right sequence of the treatments in all RAS (KRAS/NRAS) wild type (wt) patients has not precisely defined. We evaluated the impact of aforementioned targeted therapies in second line setting, analyzing efficacy and safety data from phase III clinical trials. We performed both direct and indirect comparisons between anti-EGFR and anti-VEGF. Outcomes included disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and G3-G5 toxicities. Our results showed significantly improved OS (HR 0.83, 95% CI 0.72–0.94) and DCR (HR 1.27, 95% CI 1.04–1.54) favouring anti-VEGF combinations in overall population; no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70–1.09). Anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31–0.96), showing a trend also in all RAS wt patients (RR 0.63, 95% CI 0.48–0.83). No significant difference in PFS and DCR all RAS was registered. Our results provided for the first time a strong rationale to manage both targeted agents in second line setting. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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25 pages, 2084 KiB

Open AccessReview

The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer

by Fatima Domenica Elisa De Palma, Valeria D’Argenio, Jonathan Pol, Guido Kroemer, Maria Chiara Maiuri and Francesco Salvatore

Cancers 2019, 11(7), 1017; https://doi.org/10.3390/cancers11071017 - 20 Jul 2019

Cited by 115 | Viewed by 20692

Abstract

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated [...] Read more.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated pathway”, has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (BRAF or KRAS mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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36 pages, 2076 KiB

Open AccessReview

Gold as a Possible Alternative to Platinum-Based Chemotherapy for Colon Cancer Treatment

by Inés Mármol, Javier Quero, María Jesús Rodríguez-Yoldi and Elena Cerrada

Cancers 2019, 11(6), 780; https://doi.org/10.3390/cancers11060780 - 05 Jun 2019

Cited by 46 | Viewed by 6108

Abstract

Due to the increasing incidence and high mortality associated with colorectal cancer (CRC), novel therapeutic strategies are urgently needed. Classic chemotherapy against CRC is based on oxaliplatin and other cisplatin analogues; however, platinum-based therapy lacks selectivity to cancer cells and leads to deleterious [...] Read more.

Due to the increasing incidence and high mortality associated with colorectal cancer (CRC), novel therapeutic strategies are urgently needed. Classic chemotherapy against CRC is based on oxaliplatin and other cisplatin analogues; however, platinum-based therapy lacks selectivity to cancer cells and leads to deleterious side effects. In addition, tumor resistance to oxaliplatin is related to chemotherapy failure. Gold(I) derivatives are a promising alternative to platinum complexes, since instead of interacting with DNA, they target proteins overexpressed on tumor cells, thus leading to less side effects than, but a comparable antitumor effect to, platinum derivatives. Moreover, given the huge potential of gold nanoparticles, the role of gold in CRC chemotherapy is not limited to gold(I) complexes. Gold nanoparticles have been found to be able to overcome multidrug resistance along with reduced side effects due to a more efficient uptake of classic drugs. Moreover, the use of gold nanoparticles has enhanced the effect of traditional therapies such as radiotherapy, photothermal therapy, or photodynamic therapy, and has displayed a potential role in diagnosis as a consequence of their optic properties. Herein, we have reviewed the most recent advances in the use of gold(I) derivatives and gold nanoparticles in CRC therapy. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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20 pages, 1928 KiB

Open AccessReview

Control of Tyrosine Kinase Signalling by Small Adaptors in Colorectal Cancer

by Rudy Mevizou, Audrey Sirvent and Serge Roche

Cancers 2019, 11(5), 669; https://doi.org/10.3390/cancers11050669 - 14 May 2019

Cited by 6 | Viewed by 4340

Abstract

Tyrosine kinases (TKs) phosphorylate proteins on tyrosine residues as an intracellular signalling mechanism to coordinate intestinal epithelial cell communication and fate decision. Deregulation of their activity is ultimately connected with carcinogenesis. In colorectal cancer (CRC), it is still unclear how aberrant TK activities [...] Read more.

Tyrosine kinases (TKs) phosphorylate proteins on tyrosine residues as an intracellular signalling mechanism to coordinate intestinal epithelial cell communication and fate decision. Deregulation of their activity is ultimately connected with carcinogenesis. In colorectal cancer (CRC), it is still unclear how aberrant TK activities contribute to tumour formation because TK-encoding genes are not frequently mutated in this cancer. In vertebrates, several TKs are under the control of small adaptor proteins with potential important physiopathological roles. For instance, they can exert tumour suppressor functions in human cancer by targeting several components of the oncogenic TK signalling cascades. Here, we review how the Src-like adaptor protein (SLAP) and the suppressor of cytokine signalling (SOCS) adaptor proteins regulate the SRC and the Janus kinase (JAK) oncogenic pathways, respectively, and how their loss of function in the intestinal epithelium may influence tumour formation. We also discuss the potential therapeutic value of these adaptors in CRC. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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16 pages, 859 KiB

Open AccessReview

Oxaliplatin-Based Intra-arterial Chemotherapy in Colo-Rectal Cancer Liver Metastases: A Review from Pharmacology to Clinical Application

by Girolamo Ranieri, Mariarita Laforgia, Patrizia Nardulli, Simona Ferraiuolo, Pasquale Molinari, Ilaria Marech and Cosmo Damiano Gadaleta

Cancers 2019, 11(2), 141; https://doi.org/10.3390/cancers11020141 - 24 Jan 2019

Cited by 26 | Viewed by 4566

Abstract

Liver metastases (LM) are often consequences of colo-rectal cancer (CRC)and the majority of patients have unresectable LM. Oxaliplatin-based intravenous chemotherapy represents the gold standard treatment for CRC. Intravenous oxaliplatin has several side effects i.e., nephrologic, hematologic and neurological toxicity. Moreover, hepatic arterial infusion [...] Read more.

Liver metastases (LM) are often consequences of colo-rectal cancer (CRC)and the majority of patients have unresectable LM. Oxaliplatin-based intravenous chemotherapy represents the gold standard treatment for CRC. Intravenous oxaliplatin has several side effects i.e., nephrologic, hematologic and neurological toxicity. Moreover, hepatic arterial infusion (HAI) of antitumor drugs deeply modifies the treatment of LMCRC due to the knowledge that LM are perfused by the hepatic artery network, whereas healthy tissue is perfused by the portal vein. Therefore, oxaliplatin-based HAI becomes an interesting possibility to treat LMCRC. The aim of this review is to shed light on the important impact of the oxaliplatin-based chemotherapy from a non-conventional clinical point of view, considering that, being universally accepted its antitumor effect if administered intravenously, fragmentary information are known about its clinical applications and benefits deriving from intra-arterial administration in loco-regional chemotherapy. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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16 pages, 2439 KiB

Open AccessReview

Small Bowel Carcinomas Associated with Immune-Mediated Intestinal Disorders: The Current Knowledge

by Paolo Giuffrida, Alessandro Vanoli, Giovanni Arpa, Arturo Bonometti, Ombretta Luinetti, Enrico Solcia, Gino Roberto Corazza, Marco Paulli and Antonio Di Sabatino

Cancers 2019, 11(1), 31; https://doi.org/10.3390/cancers11010031 - 29 Dec 2018

Cited by 18 | Viewed by 3742

Abstract

Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders including coeliac disease (CD) and Crohn’s disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in [...] Read more.

Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders including coeliac disease (CD) and Crohn’s disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in tumour cell phenotype, frequency of microsatellite instability and nuclear β-catenin expression, as well as in prognosis. For these patients, high tumour-infiltrating lymphocyte density and glandular/medullary histotype represent independent positive prognostic factors. Dysplasia adjacent to SBC is rare and characterized by intestinal phenotype and nuclear β-catenin in CD, while it is frequent and typified by gastro-pancreatobiliary marker expression and preserved membranous β-catenin in CrD. Recent evidence suggests that Epstein-Barr virus-positive dysplasia and SBC, albeit exceptional, do exist and are associated with CrD. In this review, we summarize the novel pathological and molecular insights of clinical and therapeutic interest to guide the care of CD-SBC and CrD-SBC. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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33 pages, 2257 KiB

Open AccessReview

Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer

by Bernadette Neve, Nicolas Jonckheere, Audrey Vincent and Isabelle Van Seuningen

Cancers 2018, 10(11), 440; https://doi.org/10.3390/cancers10110440 - 14 Nov 2018

Cited by 41 | Viewed by 5909

Abstract

Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and [...] Read more.

Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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