The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy
1
I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany
2
Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, 55131 Mainz, Germany
*
Author to whom correspondence should be addressed.
†
Authors contributed equally.
Academic Editors: Maja T. Tomicic and Thomas Efferth
Cancers 2021, 13(10), 2296; https://doi.org/10.3390/cancers13102296
Received: 31 March 2021
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Revised: 28 April 2021
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Accepted: 3 May 2021
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Published: 11 May 2021
(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)
Simple Summary
Despite remarkable progress being made by preventive medical check-ups in the last decades, colorectal cancer (CRC) remains one of the most frequent and deadliest cancers worldwide. An understanding of the mutational landscape in CRC is needed to develop new mutanome-directed therapies with stronger efficacy and less side-effects than current therapeutic standard regimes. Carcinogenesis in CRC is a multi-gene driven process, where premalignant cells accumulate successively key tumorigenesis-related mutations. Here, inactivation of the tumor suppressor gene p53 is a hallmark event during tumorigenesis. Mutations of p53 impact the prognosis of patients, enabling the use of targeted therapies such as immune therapy. Alterations of p53 affect not only the tumor biology of cancer cells but also the surrounding tumor microenvironment (TME).
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.
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Keywords:
colorectal cancer; p53; systemic therapy; immunotherapy; tumor microenvironment (TME); cancer-associated fibroblasts; signaling; targeted therapy
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MDPI and ACS Style
Michel, M.; Kaps, L.; Maderer, A.; Galle, P.R.; Moehler, M. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. Cancers 2021, 13, 2296. https://doi.org/10.3390/cancers13102296
AMA Style
Michel M, Kaps L, Maderer A, Galle PR, Moehler M. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. Cancers. 2021; 13(10):2296. https://doi.org/10.3390/cancers13102296
Chicago/Turabian StyleMichel, Maurice, Leonard Kaps, Annett Maderer, Peter R. Galle, and Markus Moehler. 2021. "The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy" Cancers 13, no. 10: 2296. https://doi.org/10.3390/cancers13102296
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