scholarly journals The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2296
Author(s):  
Maurice Michel ◽  
Leonard Kaps ◽  
Annett Maderer ◽  
Peter R. Galle ◽  
Markus Moehler
Keyword(s):  
Colorectal Cancer ◽  
Stromal Cells ◽  
Tp53 Gene ◽  
Cancer Associated Fibroblasts ◽  
P53 Mutations ◽  
The One ◽  
Immunosuppressive Cells ◽  
And Personalized Medicine ◽  
Therapy Treatment

Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.

scholarly journals Genetics of Colorectal Cancer: Role of p53

2020 ◽  
Vol 10 (6-s) ◽  
pp. 183-185
Author(s):  
Rajashri Champanery ◽  
Drashti Joshi
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tp53 Mutation ◽  
Human Cancer ◽  
Tumor Development ◽  
Tp53 Gene ◽  
Pathological Process ◽  
Functional Roles ◽  
Different Types

The tumor suppressor TP53 gene is one of the most frequently mutated in different types of human cancer. Particularly in colorectal cancer (CRC), it is believed that TP53 mutations play a role in the adenoma-carcinoma transition of tumors during pathological process. The TP53 mutation is the key step driving the transition from adenoma to adenocarcinoma. The functional roles of TP53 mutation in tumor development have been comprehensively investigated. In this mini review, we comprehensively summarize the p53 mutants in CRC progression and discuss the current strategies for p53 mutants in malignancies. Keywords: p53 mutants, colorectal cancer, Tp53 mutation

Role of p53 Mutations in Colorectal Cancer

2017 ◽  
Vol 6 (1) ◽  
pp. 105-110
Author(s):  
Anitha S. ◽  
◽  
Sridevi P. ◽  
Durga K. ◽  
◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
P53 Mutations

scholarly journals The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6206
Author(s):  
Raghav Chandra ◽  
John D. Karalis ◽  
Charles Liu ◽  
Gilbert Z. Murimwa ◽  
Josiah Voth Park ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Distant Metastases ◽  
Cancer Associated Fibroblasts ◽  
Clinical Strategies ◽  
Cancer Tumor ◽  
Cellular Components ◽  
Common Malignancy ◽  
Related Mortality

Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.

scholarly journals Resveratrol Suppresses Cross-Talk between Colorectal Cancer Cells and Stromal Cells in Multicellular Tumor Microenvironment: A Bridge between In Vitro and In Vivo Tumor Microenvironment Study

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4292
Author(s):  
Constanze Buhrmann ◽  
Parviz Shayan ◽  
Aranka Brockmueller ◽  
Mehdi Shakibaei
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
T Lymphocytes ◽  
Cancer Cells ◽  
T Lymphocyte ◽  
Stromal Cells ◽  
Colorectal Cancer Cells ◽  
Hct116 Cells

The interaction between tumor cells and the tumor microenvironment (TME) is an important process for the development of tumor malignancy. Modulation of paracrine cross-talk could be a promising strategy for tumor control within the TME. The exact mechanisms of multi-targeted compound resveratrol are not yet fully understood. Whether resveratrol can modulate paracrine signal transduction-induced malignancy in the multicellular-TME of colorectal cancer cells (CRC) was investigated. An in vitro model with 3D-alginate HCT116 cells in multicellular-TME cultures (fibroblast cells, T-lymphocytes) was used to elucidate the role of TNF-β, Sirt1-ASO and/or resveratrol in the proliferation, invasion and cancer stem cells (CSC) of CRC cells. We found that multicellular-TME, similar to TNF-β-TME, promoted proliferation, colony formation, invasion of CRC cells and enabled activation of CSCs. However, after co-treatment with resveratrol, the malignancy of multicellular-TME reversed to HCT116. In addition, resveratrol reduced the secretion of T-lymphocyte/fibroblast (TNF-β, TGF-β3) proteins, antagonized the T-lymphocyte/fibroblast-promoting NF-κB activation, NF-κB nuclear translocation and thus the expression of NF-κB-promoting biomarkers, associated with proliferation, invasion and survival of CSCs in 3D-alginate cultures of HCT116 cells induced by TNF-β- or multicellular-TME, but not by Sirt1-ASO, indicating the central role of this enzyme in the anti-tumor function of resveratrol. Our results suggest that in vitro multicellular-TME promotes crosstalk between CRC and stromal cells to increase survival, migration of HCT116 and the resveratrol/Sirt1 axis suppresses this loop by modulating paracrine agent secretion and NF-κB signaling. Fibroblasts and T-lymphocytes are promising targets for resveratrol in the prevention of CRC metastasis.

scholarly journals A Novel Mechanism of the c-Myc/NEAT1 Axis Mediating Colorectal Cancer Cell Response to Photodynamic Therapy Treatment

2021 ◽  
Vol 11 ◽  
Author(s):  
Kuijie Liu ◽  
Sanlin Lei ◽  
Yong Kuang ◽  
Qianqian Jin ◽  
Dongju Long ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Photodynamic Therapy ◽  
Cell Viability ◽  
Critical Role ◽  
Tumor Model ◽  
P53 Signaling ◽  
Sw480 Cells ◽  
Therapy Treatment ◽  
Hct116 Cells

Photodynamic therapy (PDT) is considered a potential treatment regimen for colorectal cancer cases (CRC). p53 signaling and the miR-124/iASPP axis play an essential role in the PDT resistance of CRC cells. PDT treatment downregulated NEAT1 expression in p53wt HCT116 and RKO cells. In these two cell lines, NEAT1 silencing enhanced the suppressive effects of PDT on cell viability and apoptosis. Within the subcutaneously implanted tumor model, NEAT1 silencing enhanced PDT-induced suppression on tumor growth. Regarding p53-deleted HCT116 cells, PDT only moderately affected cell proliferation but induced downregulation of NEAT1. NEAT1 directly targeted miR-124, acting as a ceRNA, competing with iASPP for miR-124 binding, and counteracting miR-124–mediated repression on iASPP under PDT treatment. NEAT1 silencing was enhanced, whereas miR-124 inhibition attenuated PDT effects on CRC cells; miR-124 inhibition significantly reversed the roles of NEAT1 silencing in PDT-treated CRC cells. miR-124 negatively correlated with NEAT1 and iASPP, respectively, whereas NEAT1 and iASPP positively correlated with each other. PDT downregulated c-Myc in CRC cells, and c-Myc activated the transcription of NEAT1 through the targeting of its promoter region. Within p53mut SW480 cells, PDT failed to alter cell viability and apoptosis but still downregulated c-Myc, NEAT1, and iASPP and upregulated miR-124. In p53 mutant high-abundant CRC tissues, c-Myc and NEAT1 were up-regulated, and miR-124 was downregulated. In c-Myc high-abundant CRC tissues, NEAT1 and iASPP were up-regulated, and miR-124 was downregulated. The critical role of the c-Myc/NEAT1 axis in mediating CRC response to PDT treatment via the miR-124/iASPP/p53 feedback loop was conclusively demonstrated.

scholarly journals The Colorectal Cancer Microenvironment: Strategies for Studying the Role of Cancer-Associated Fibroblasts

2018 ◽  
pp. 87-98 ◽  
Author(s):  
Rahul Bhome ◽  
Massimiliano Mellone ◽  
Katherine Emo ◽  
Gareth J. Thomas ◽  
A. Emre Sayan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Microenvironment ◽  
Cancer Associated Fibroblasts

scholarly journals OUR EXPERIENCE IN THE SURGICAL MANAGEMENT OF PATIENTS WITH RECTAL NEOPLASTIC DISEASE

2016 ◽  
Vol 3 (2) ◽  
pp. 64-71
Author(s):  
Alina Cristina Tinca ◽  
R. Palade ◽  
D. Ion ◽  
Adriana Elena Nica ◽  
Alexandra Bolocan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Technological Development ◽  
Surgical Techniques ◽  
The Other ◽  
Neoplastic Disease ◽  
Single Center ◽  
Rectal Neoplasia ◽  
The One

Colorectal cancer is one of the most commonly incriminated neoplastic pathologies and it has afairly high mortality rate. Although the therapeutic arsenal of rectal cancer has steadily improvedthrough the acquisition of biology, technology and pharmacology, the central role of surgicaltechnique is widely recognized in obtaining local control, on the one hand and a good quality of lifeof operated patient on the other hand. This article is a retrospective analysis of surgical proceduresfor rectal neoplasia conducted in order to determine to what extent technological development andcontinuous improvement of surgical techniques have influenced the evolution of patientmanagement with this pathology. This study was retrospective, observational, descriptive, single-center and it was held in the Department of General Surgery and Emergency III of the UniversityEmergency Hospital Bucharest during 1 January 2007 - March 31, 2016 and included a total of127 patients.

scholarly journals miRNAs derived from cancer-associated fibroblasts in colorectal cancer

Epigenomics ◽  
2019 ◽  
Vol 11 (14) ◽  
pp. 1627-1645 ◽  
Author(s):  
Amir Savardashtaki ◽  
Zahra Shabaninejad ◽  
Ahmad Movahedpour ◽  
Roxana Sahebnasagh ◽  
Hamed Mirzaei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Tumor Development ◽  
Complex Interaction ◽  
Cancer Associated Fibroblasts ◽  
Paracrine Signaling ◽  
Cancer Stroma ◽  
The World ◽  
First Time

Currently, the incidence of colorectal cancer (CRC) is increasing across the world. The cancer stroma exerts an impact on the spread, invasion and chemoresistance of CRC. The tumor microenvironment involves a complex interaction between cancer cells and stromal cells, for example, cancer-associated fibroblasts (CAFs). CAFs can promote neoplastic angiogenesis and tumor development in CRC. Mounting evidence suggests that many miRNAs are overexpressed (miR-21, miR-329, miR-181a, miR-199a, miR-382 and miR-215) in CRC CAFs, and these miRNAs can influence the spread, invasiveness and chemoresistance in neighboring tumor cells via paracrine signaling. Herein, we summarize the pathogenic roles of miRNAs and CAFs in CRC. Moreover, for first time, we highlight the miRNAs derived from CRC-associated CAFs and their roles in CRC pathogenesis.

Cancer-Secreted Exosomal HSPC111 Promotes Colorectal Cancer Liver Metastasis By Reprogramming Lipid Metabolism in Cancer-Associated Fibroblasts

2021 ◽  
Author(s):  
Chong Zhang ◽  
Xiang-Yu Wang ◽  
Peng Zhang ◽  
Tao-Chen He ◽  
Jia-Hao Han ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lipid Metabolism ◽  
Liver Metastasis ◽  
Metabolic Reprogramming ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Cancer Associated Fibroblasts ◽  
Metastatic Niche

Abstract Background: Metastasis and metabolic deregulation are two of the major hallmarks of cancer. Recent studies have revealed the critical driving role of metabolic reprogramming of tumor cells to promote colorectal cancer (CRC) metastasis. However, little is known about the metabolic alterations of cancer-associated fibroblasts (CAFs) in the pre-metastatic niche and how these changes facilitate CRC metastasis.Methods: Liquid chromatography-mass spectrometry (LC-MS) and Isobaric Tags for Relative and Absolute Quantitation (i-TRAQ) method were performed to identify the comparative metabolites and proteins expression in CAFs treated with exosomes derived from CRC cells, respectively. Tissue Microarray (TMA) was used to evaluate the level of HSPC111 in patient’s primary CRC tissues with or without liver metastasis. Co-immunoprecipitation (Co-IP), RNA-seq, chromatin immunoprecipitation (ChIP) migration and wound healing assay and immunofluorescence staining were employed to explore the expression regulation mechanism of exosomal HSPC111 in CAFs. Xenograft models were used to determine whether exosomal HSPC111 can remolding pre-metastatic niche of CAFs to promote CRC liver metastasis (CRLM) in vivo.Results: Here, we demonstrate that CRC cell-secreted exosomal HSPC111 induces a lipid metabolism reprogramming process in CAFs. Importantly, our results indicate that CRC patients with liver metastasis had significantly high level of HSPC111 in CRC tissues than CRC patients without liver metastasis. Mechanistically, HSPC111 upregulate the level of acetyl-CoA and histone acetylation by phosphorylating of ATP-citrate lyase (ACLY) in CAFs. This lipid metabolism reprogramming in CAFs facilitates CXCL5 secretion in vitro and pre-metastatic niche formation in the liver to promote CRLM in an exosomal HSPC111-dependent manner in vivo. In addition, conditioned medium (CM) from CAFs induce EMT of CRC cells by down-regulating E-cadherin levels and up-regulating Vimentin and Snail levels, which could be abolished by CXCL5-neutralizing antibody and CXCR2 inhibitor navarixin. Moreover, the HSPC111-ACLY association in CAFs was reinforced by CXCL5-CXCR2 axis, further promoting exosomal HSPC111 secretion from CRC cells to form a feedforward regulatory loop.Conclusion: Our present study reveals a novel insight into the pro-metastatic role of lipid metabolism reprogramming in CAFs and suggests the CXCL5-CXCR2 axis may be a promising target for halting CRLM.

scholarly journals Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

Oncogenesis ◽  
2020 ◽  
Vol 9 (11) ◽  
Author(s):  
Pawan Noel ◽  
Shaimaa Hussein ◽  
Serina Ng ◽  
Corina E. Antal ◽  
Wei Lin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Cancer Associated Fibroblasts ◽  
Cell Type ◽  
Pancreatic Cancer Cells ◽  
Cell Type Specific

Abstract The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous, fibrotic, and hypovascular, marked by extensive desmoplasia and maintained by the tumor cells, cancer-associated fibroblasts (CAFs) and other stromal cells. There is an urgent need to identify and develop treatment strategies that not only target the tumor cells but can also modulate the stromal cells. A growing number of studies implicate the role of regulatory DNA elements called super-enhancers (SE) in maintaining cell-type-specific gene expression networks in both normal and cancer cells. Using chromatin activation marks, we first mapped SE networks in pancreatic CAFs and epithelial tumor cells and found them to have distinct SE profiles. Next, we explored the role of triptolide (TPL), a natural compound with antitumor activity, in the context of modulating cell-type-specific SE signatures in PDAC. We found that TPL, cytotoxic to both pancreatic tumor cells and CAFs, disrupted SEs in a manner that resulted in the downregulation of SE-associated genes (e.g., BRD4, MYC, RNA Pol II, and Collagen 1) in both cell types at mRNA and protein levels. Our observations suggest that TPL acts as a SE interactive agent and may elicit its antitumor activity through SE disruption to re-program cellular cross talk and signaling in PDAC. Based on our findings, epigenetic reprogramming of transcriptional regulation using SE modulating compounds such as TPL may provide means for effective treatment options for pancreatic cancer patients.

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