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

Michel, Maurice Stephan; Kaps, Leonard; Maderer, Annett; Galle, Peter R.; Moehler, Markus

doi:10.3390/cancers13102296

Cited by 67 publications

(35 citation statements)

References 195 publications

(230 reference statements)

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“…Among the 10 genes, we found that 8 genes had SNPs in LGD and HGD. The associations of 5 of these genes ( TP53 , 14 KRAS , 15 GSTP1 , 16 MTHFR , 17 and ABCC2 18 ) with colonic adenoma have previously been reported in several studies, whereas no such association of XRCC1, UMPS , or DPYD has been reported to date ( Supplementary Table 1 ). In addition, we selected XRCC1 as the focus of this study given previous results from a meta-analysis demonstrating a relationship between the XRCC1 rs25487 polymorphism and sensitivity to platinum-based chemotherapy drugs in CRC patients.…”

Section: Resultsmentioning

confidence: 95%

Clinical Impact of X-Ray Repair Cross-Complementary 1 (XRCC1) and the Immune Environment in Colorectal Adenoma–Carcinoma Pathway Progression

Zhang¹,

Jin²,

Chen³

et al. 2021

JIR

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Colorectal cancer (CRC) can develop via a hypermutagenic pathway characterized by frequent somatic DNA base-pair mutations. Alternatively, the immunogenicity of tumor cells themselves may influence the anticancer activity of the immune effector cells. Impaired DNA repair mechanisms drive mutagenicity, which then increase the neoantigen load and immunogenicity. However, no studies have analyzed immune checkpoint protein expression, particularly programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), in adenoma-carcinoma progression and its relationship with the emergence of other DNA repair gene mutation. Materials and Methods: We investigated mutations of 10 genes involved in DNA repair function: XRCC1, TP53, MLH1, MSH, KRAS, GSTP, UMP, MTHF, DPYD, and ABCC2. We performed sequencing to determine mutations and immunohistochemistry of immune checkpoints in clinical samples and determined changes in XRCC1 expression during progression through the adenoma-carcinoma pathway. We further investigated the prognostic associations of gene XRCC1 according to the expression, mutational profile, and immune profile using The Cancer Genome Atlas-colon adenocarcinoma (TCGA-COAD) dataset. Results: From clinical samples, XRCC1 mutation demonstrated the strongest association with adenomas with a mutation frequency of 56.2% in adenomas and 34% in CRCs (p =0.016). XRCC1 was abnormally expressed and altered by mutations contributing to adenoma carcinogenesis. High expression of XRCC1, CD4, FOXP3, and PD-1/PD-L1 showed an overall upward trend with increased lesion severity (all p < 0.01). PD-1/PD-L1 expression and CD4+ intraepithelial lymphocytes (IELs) correlated with cytological dysplasia progression, specifically in patients with wild-type XRCC1 (all p < 0.01), whereas FOXP3 expression was independently associated with adenoma-carcinoma progression. From TCGA-COAD analysis, XRCC1 expression was associated with patients survival, tumor-infiltrating lymphocytes and immune marker expression. Conclusion: Increased IEL density and PD-1/PD-L1 expression correlate with cytological dysplasia progression and specifically with the XRCC1 mutation status in CRC. Our findings support a stepwise dysplasia-carcinoma sequence of adenoma carcinogenesis and an XRCC1 hypermutated phenotypic mechanism of lesions.

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Section: Resultsmentioning

confidence: 95%

Clinical Impact of X-Ray Repair Cross-Complementary 1 (XRCC1) and the Immune Environment in Colorectal Adenoma–Carcinoma Pathway Progression

Zhang¹,

Jin²,

Chen³

et al. 2021

JIR

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“…In addition to KRAS and PIK3CA mutations, CRC cells used in this study harbored mutations in TP53. Preclinical studies suggested that there are correlations between resistant to therapies and TP53 alterations in mCRC [40][41][42] . Our results showed that liver ECs induced HER3-AKT activation and cell survival in all cell lines we used, which harbor either wild-type or mutant TP53.…”

Section: Discussionmentioning

confidence: 99%

Liver Endothelium Promotes HER3-mediated Cell Survival inKRASWild-type and Mutant Colorectal Cancer Cells

Rathore

Bhattacharya

et al. 2021

Preprint

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We previously showed that primary liver endothelial cells (ECs) secreted soluble factors in a paracrine fashion (angiocrine) and activated human epidermal growth factor receptor 3 (HER3, also known as ERBB3) mediated colorectal cancer (CRC) growth and chemoresistance. However, Ras proteins play a critical role in receptor tyrosine kinase signaling pathways, and KRAS mutations mediate CRC resistance to therapies targeting EGFR, another HER protein. Therefore, the role of KRAS mutation status in EC-induced HER3 activation and CRC survival was investigated as it has therapeutic implications. We used CRC cell lines and patient-derived xenografts harboring KRAS wild-type or mutant genes and demonstrated that liver EC-secreted factors promoted HER3-mediated CRC cell growth independent of KRAS mutation status. Also, blocking HER3 in CRC by siRNAs or a HER3 antibody seribantumab attenuated EC-induced CRC cell survival. Our findings highlight the potential of utilizing HER3-targeted therapies for treating patients with mCRC independent of RAS mutational status

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“…The increase of genomic instability and the successive mutations in genes such as KRAS and SMADs trigger the formation of dysplastic tubular adenomas [ 61 , 74 , 75 ]. As a result, alterations in the Transforming growth factor-β (TGF-β) pathway and the inactivation of the TP53 gene culminate in the formation of invasive adenocarcinomas [ 61 , 75 , 76 , 77 ]. Once epithelial tumor tissue is in constant interaction with cells in tumor microenvironment (TME) through the action of cytokines, chemokines, and growth factors, additional mutations, and changes in TME components give advantage to tumor clones and allow the tumors to later metastasize to distant organs [ 78 , 79 , 80 , 81 , 82 ] ( Figure 2 ).…”

Section: The Wnt/β-catenin Signaling Pathwaymentioning

confidence: 99%

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer

Oliveira

Predes

Borges

et al. 2022

Cancers

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Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.

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

Cited by 67 publications

References 195 publications

Clinical Impact of X-Ray Repair Cross-Complementary 1 (XRCC1) and the Immune Environment in Colorectal Adenoma–Carcinoma Pathway Progression

Clinical Impact of X-Ray Repair Cross-Complementary 1 (XRCC1) and the Immune Environment in Colorectal Adenoma–Carcinoma Pathway Progression

Liver Endothelium Promotes HER3-mediated Cell Survival inKRASWild-type and Mutant Colorectal Cancer Cells

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer

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