RAS, Cellular Plasticity, and Tumor Budding in Colorectal Cancer

Maffeis, Valeria; Nicolè, Lorenzo; Cappellesso, Rocco

doi:10.3389/fonc.2019.01255

Cited by 51 publications

(56 citation statements)

References 148 publications

(193 reference statements)

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“…CMS1 (MSI-H/CIMP-H and MSS/MSI-L/0/CIMP-H) 38,40 tumors have characteristics previously reported by Jass 41 for MSI-H/CIMP-H tumors in sporadic CRC. Sessile serrated adenomas/polyps have been described as a precursor lesion for this group.…”

Section: Discussionsupporting

confidence: 54%

Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability

Wielandt

Hurtado

et al. 2020

Tumour Biol.

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Molecular classification of colorectal cancer is difficult to implement in clinical settings where hundreds of genes are involved, and resources are limited. This study aims to characterize the molecular subtypes of patients with sporadic colorectal cancer based on the three main carcinogenic pathways microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) in a Chilean population. Although several reports have characterized colorectal cancer, most do not represent Latin-American populations. Our study includes 103 colorectal cancer patients who underwent surgery, without neoadjuvant treatment, in a private hospital between 2008 and 2017. MSI, CIN, and CIMP status were assessed. Frequent mutations in KRAS, BRAF, and PIK3CA genes were analyzed by Sanger sequencing, and statistical analysis was performed by Fisher’s exact and/or chi-square test. Survival curves were estimated with Kaplan–Meier and log-rank test. Based on our observations, we can classify the tumors in four subgroups, Group 1: MSI-high tumors (15%) are located in the right colon, occur at older age, and 60% show a BRAF mutation; Group 2: CIN-high tumors (38%) are in the left colon, and 26% have KRAS mutations. Group 3: [MSI/CIN/CIMP]-low/negative tumors (30%) are left-sided, and 39% have KRAS mutations; Group 4: CIMP-high tumors (15%) were more frequent in men and left side colon, with 27% KRAS and 7% presented BRAF mutations. Three percent of patients could not be classified. We found that CIMP-high was associated with a worse prognosis, both in MSI-high and MSI stable patients (p = 0.0452). Group 3 (Low/negative tumors) tend to have better overall survival compared with MSI-high, CIMP-high, and CIN-high tumors. This study contributes to understanding the heterogeneity of tumors in the Chilean population being one of the few characterizations performed in Latin-America. Given the limited resources of these countries, these results allow to improve molecular characterization in Latin-American colorectal cancer populations and confirm the possibility of using the three main carcinogenic pathways to define therapeutic strategies.

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Section: Discussionsupporting

confidence: 54%

Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability

Wielandt

Hurtado

et al. 2020

Tumour Biol.

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“…Epithelial and mesenchymal cells even co-exist within the same clone in most tumors of Pten/Trp53-deficient mice [77], suggesting that the induction of pEMT is likely to be an inherent property of most clones. This is somehow at odds with the traditional view that EMT usually occurs at the invasive front in the tumor buds, the morphological surrogate of EMT featuring cellular plasticity [78]. Acquisition of an E/Mstate is facilitated by the expression of EMT-inducing TFs and the activation of adult stem cell programs, i.e., canonical Wnt signaling.…”

Section: Emt As a Transdifferentiation Processmentioning

confidence: 94%

The Intimate Relationship among EMT, MET and TME: A T(ransdifferentiation) E(nhancing) M(ix) to Be Exploited for Therapeutic Purposes

Hass

Ohe

Ungefroren

2020

Cancers

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Intratumoral heterogeneity is considered the major cause of drug unresponsiveness in cancer and accumulating evidence implicates non-mutational resistance mechanisms rather than genetic mutations in its development. These non-mutational processes are largely driven by phenotypic plasticity, which is defined as the ability of a cell to reprogram and change its identity (phenotype switching). Tumor cell plasticity is characterized by the reactivation of developmental programs that are closely correlated with the acquisition of cancer stem cell properties and an enhanced potential for retrodifferentiation or transdifferentiation. A well-studied mechanism of phenotypic plasticity is the epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and clues from the tumor microenvironment in cell reprogramming. A deeper understanding of the connections between stem cell, epithelial–mesenchymal, and tumor-associated reprogramming events is crucial to develop novel therapies that mitigate cell plasticity and minimize the evolution of tumor heterogeneity, and hence drug resistance. Alternatively, vulnerabilities exposed by tumor cells when residing in a plastic or stem-like state may be exploited therapeutically, i.e., by converting them into less aggressive or even postmitotic cells. Tumor cell plasticity thus presents a new paradigm for understanding a cancer’s resistance to therapy and deciphering its underlying mechanisms.

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“…In our study the frequency of KRAS mutations in metastatic or recurrent disease is much similar to that of patients without local or systemic relapse. This suggests that KRAS mutations alone are not sufficient for changes in the epithelial morphology of colorectal cancer cells regarded as necessary for metastasis evolvement [43]. Thus, KRAS mutations alone do not seem to cause metastasis.…”

Section: Plos Onementioning

confidence: 99%

KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer

Jo¹,

Bernhardt²,

Nietert³

et al. 2020

PLoS ONE

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Introduction Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre-and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing. Materials and methods KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens. Results The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence

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RAS, Cellular Plasticity, and Tumor Budding in Colorectal Cancer

Cited by 51 publications

References 148 publications

Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability

Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability

The Intimate Relationship among EMT, MET and TME: A T(ransdifferentiation) E(nhancing) M(ix) to Be Exploited for Therapeutic Purposes

KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer

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