Molecular Heterogeneity of High Grade Colorectal Adenocarcinoma

Perna, Cristian; Navarro, Antònia; Ruz-Caracuel, Ignacio; Caniego-Casas, Tamara; Cristóbal, Eva; Leskelä, Susanna; Longo, Federico; Caminoa, Alejandra; Santón, Almudena; Ferreiro, Reyes; Pizarro, David; Palacios-Berraquero, María Luisa; Palacios, José

doi:10.3390/cancers13020233

Cited by 8 publications

(7 citation statements)

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“…Clonal diversity was due to the accumulation of mutations in genes of diverse pathways, such as Notch and MMR pathways (28). Notch signaling can provide the first mechanistic example of altered glycosylation in tumor cells with MSI (29).…”

Section: Mismatch Repair Was Regulated By Rnps1 Knockdown Through Notch Signaling Pathway In Vivomentioning

confidence: 99%

RNA-binding protein with serine-rich domain 1 regulates microsatellite instability of uterine corpus endometrial adenocarcinoma

Liu¹,

Ma²,

Ma³

et al. 2021

Clinics

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To determine the role of RNA-binding protein with serine-rich domain 1 (RNPS1) in uterine corpus endometrial carcinoma (UCEC), the role of RNPS1 knockdown in UCEC development in vitro and in vivo, and the relationship between RNPS1 and mismatch repair (MMR) in UCEC. METHODS: We predicted the potential function of RNPS1 using bioinformatics systems. The expression of RNPS1 in tissues and cell lines was analyzed by western blotting and immunohistochemistry. The expression of RNPS1 in MMR was assessed using bioinformatics and western blotting. The proliferation and apoptosis of UCEC cells were assessed under RNPS1 knockdown conditions, and RNPS1 regulation in MMR was detected by suppressing Notch signaling. Associations between RNPS1 and gene mutations in UCEC and prognosis were analyzed. RESULTS: The RNPS1 level was higher in UCEC tumors than in normal tissues and tumors or RL952 cells. Prognostic outcomes were worse when UCEC showed abundant RNPS1 expression. Lentiviral RNPS1 knockdown weakened tumor cell proliferation and suppressed biomarker expression, reduced the tumor volume, promoted apoptosis in vitro and in vivo, and inhibited UCEC development. Increased MutS homolog 2 (MSH2) and MutS homolog 6 (MSH6) levels in MMR after RNPS1 knockdown were reversed by inhibiting Notch signaling. Furthermore, RNPS1 was associated with mutations in NAA11, C2orf57, NUPR1, and other genes involved in UCEC prognosis. CONCLUSION: RNPS1 may regulate the expression levels of MSH2 and MSH6 in MMR, enhancing the proliferation, development, and prognosis of UCEC through a Notch signaling pathway in UCEC. Our study offers a new method and strategy for delaying UCEC development through modulating MMR.

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Section: Mismatch Repair Was Regulated By Rnps1 Knockdown Through Notch Signaling Pathway In Vivomentioning

confidence: 99%

RNA-binding protein with serine-rich domain 1 regulates microsatellite instability of uterine corpus endometrial adenocarcinoma

Liu¹,

Ma²,

Ma³

et al. 2021

Clinics

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“…Hypermutation is a hallmark of CRC, although 20% of these mutations cause cancer and far fewer mutations are common in two or more tumors ( 6 ). Patients within a mutational group are even heterogeneous ( 93 ). For example, in patients with the KRAS mutation, those with the mutation in codon 13 (G13D) respond to the combination of chemotherapy and targeted therapy, while patients with the mutation in codon 12 (G12R) do not respond well ( 94 ).…”

Section: Crc Heterogeneity: a Challenge Of Immunotherapymentioning

confidence: 99%

Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?

Lan

Huang

et al. 2021

Front. Oncol.

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Colorectal cancer (CRC) is the second leading cause of cancer death in the world. Immunotherapy using monoclonal antibodies, immune-checkpoint inhibitors, adoptive cell therapy, and cancer vaccines has raised great hopes for treating poor prognosis metastatic CRCs that are resistant to the conventional therapies. However, high inter-tumor and intra-tumor heterogeneity hinder the success of immunotherapy in CRC. Patients with a similar tumor phenotype respond differently to the same immunotherapy regimen. Mutation-based classification, molecular subtyping, and immunoscoring of CRCs facilitated the multi-aspect grouping of CRC patients and improved immunotherapy. Personalized immunotherapy using tumor-specific neoantigens provides the opportunity to consider each patient as an independent group deserving of individualized immunotherapy. In the recent decade, the development of sequencing and multi-omics techniques has helped us classify patients more precisely. The expansion of such advanced techniques along with the neoantigen-based immunotherapy could herald a new era in treating heterogeneous tumors such as CRC. In this review article, we provided the latest findings in immunotherapy of CRC. We elaborated on the heterogeneity of CRC patients as a bottleneck of CRC immunotherapy and reviewed the latest advances in personalized immunotherapy to overcome CRC heterogeneity.

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“…Only a few studies have analysed MMR status and molecular characteristics in CRC. A recent study demonstrated that only MMR-proficient CRC that lacked evidence of differentiation totally lost E-cadherin expression (Perna et al, 2021). Such a phenomenon has also been demonstrated in gastric carcinomas with MLH1 hyper-methylation (Moghbeli et al, 2014).…”

Section: Mismatch Repair Proteinsmentioning

confidence: 85%

Association of Epithelial Mesenchymal Transition, Stemness and Inflammation in Colorectal Carcinoma. Doctoral Thesis

Briede¹

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Colorectal cancer (CRC) and its treatment is one of the hot topics in medicine, as there is a still a high number of patients with CRC and deaths from CRC. In the era of personalized medicine, a huge field of research is devoted to inflammation, a process that plays an important dual role in carcinogenesis. Survival studies have highlighted the prognostic significance of peritumoural inflammation in CRC. The current theoretical background allows us to link inflammation, the epithelial-mesenchymal transition (EMT), and the closely associated stem cell differentiation in CRC. However, there is scarce direct morphological evidence. The aim of this work was to investigate the role of inflammation in cancer growth and invasion by analyzing the association between inflammation and known morphological prognostic features of CRC, EMT, and mismatch repair (MMR) protein expression. Materials and methods: This retrospective, morphological, and immunohistochemical investigation involved 553 consecutive cases of surgically treated CRC. Besides histopathological CRC assessment, peritumoural inflammation, EMT-characterizing molecular parameters, and MMR protein immunohistochemical detection within CRC tissue was performed. Descriptive statistical analysis was done. The research was carried out in accordance with the Declaration of Helsinki and received approval from the Committee of Ethics of Riga Stradins University [No E-9 (2), 04.09.2014].Results: The tumours of the 553 CRC cases were predominantly located in the left part of the bowel (70.9 %), and were significantly associated with an annular appearance and smaller size (p < 0.05). Mucinous and signet ring cell carcinomas detected within this study were associated with a larger tumour size and significant local structure involvement. Locally advanced tumours predominated within this study: pT3 comprised 49.6 % of cases, pT4 comprised 35.6 % of cases, and pN + comprised 40.5 % of cases. The extent of necrosis was significantly higher in tumours with higher pT, grade, and pN+. There were significant associations between high-grade inflammation and lower pT (p = 0.002), the absence of lymph node metastases (p< 0.001), and less frequent local structure involvement (p< 0.05). Expression of EMT markers and MMR proteins yielded no significant associations with peritumoural inflammation based on the Klintrup-Mäkinen score or the density of lymphoid follicles. Nevertheless, E-cadherin expression was significantly associated with the eosinophil density (p = 0.007), and lower N-cadherin expression was significantly associated with the presence of synchronous CRC. Lower MMR protein expression was associated with changes in E-cadherin and CD44 expression (p< 0.05). Lower MLH1 expression was associated with a lower neutrophil density within the CRC (p = 0.02).Conclusion: High-grade peritumoural inflammation is associated with beneficial morphologic CRC features, including less frequent invasion, and is not secondary to tissue damage and necrosis. Crohn’s disease-like lymphoid reaction (CLR) is not associated with cancer spread by pTN; this finding indirectly suggests an independent role of CLR in carcinogenesis. Further, inflammation based on the Klintrup-Mäkinen score and CLR are not dependent on EMT and stem cell differentiation. MMR protein expression is a marker for EMT within CRC, indicating the need to perform these tests on routine examination to detect patients who might need more advance treatment. MLH1 expression within CRC affects the density of neutrophils within peritumoural inflammation, showing a potential role for the MMR status in anti-tumour immunity. This research highlights the complex associations between inflammation, tumour morphology, EMT, and MMR protein expression in human CRC tissues.

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Molecular Heterogeneity of High Grade Colorectal Adenocarcinoma

Cited by 8 publications

References 42 publications

RNA-binding protein with serine-rich domain 1 regulates microsatellite instability of uterine corpus endometrial adenocarcinoma

RNA-binding protein with serine-rich domain 1 regulates microsatellite instability of uterine corpus endometrial adenocarcinoma

Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?

Association of Epithelial Mesenchymal Transition, Stemness and Inflammation in Colorectal Carcinoma. Doctoral Thesis

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