RAS, Cellular Plasticity, and Tumor Budding in Colorectal Cancer.

Valeria Maffeis,Lorenzo Nicolè,Rocco Cappellesso

doi:10.3389/fonc.2019.01255

Abstract

The high morbidity and mortality of colorectal cancer (CRC) remain a worldwide challenge, despite the advances in prevention, diagnosis, and treatment. RAS alterations have a central role in the pathogenesis of CRC universally recognized both in the canonical mutation-based classification and in the recent transcriptome-based classification. About 40% of CRCs are KRAS mutated, 5% NRAS mutated, and only rare cases are HRAS mutated. Morphological and molecular correlations demonstrated the involvement of RAS in cellular plasticity, which is related to invasive and migration properties of neoplastic cells. RAS signaling has been involved in the initiation of epithelial to mesenchymal transition (EMT) in CRC leading to tumor spreading. Tumor budding is the morphological surrogate of EMT and features cellular plasticity. Tumor budding is clinically relevant for CRC patients in three different contexts: (i) in pT1 CRC the presence of tumor buds is associated with nodal metastasis, (ii) in stage II CRC identifies the cases with a prognosis similar to metastatic disease, and (iii) intratumoral budding could be useful in patient selection for neoadjuvant therapy. This review is focused on the current knowledge on RAS in CRC and its link with cellular plasticity and related clinicopathological features.

Highlights

Colorectal cancer (CRC) is a malignant epithelial tumor originating in the large bowel and in almost all cases it features as an adenocarcinoma, a neoplasia with glandular characteristics [1]
Despite the big efforts of the last decades resulting in the widespread implementation of screening programs, that have proved effective in reducing the burden of the disease in the population, and in the advances of the surgical and systemic treatments, that have improved the outcome of the patients, CRC is still the third cancer for incidence and the second for mortality in both sexes worldwide [2,3,4]
We summarize the most meaningful molecular classifications of CRC highlighting the role of RAS in this tumor and its link with cellular plasticity, invasion, and migration at both molecular and morphological levels

Summary

INTRODUCTION

Colorectal cancer (CRC) is a malignant epithelial tumor originating in the large bowel and in almost all cases it features as an adenocarcinoma, a neoplasia with glandular characteristics [1]. It has been shown that in CRC cell lines mutated KRAS can activate downstream effectors of the PI3K pathway, such as Ras homolog gene family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1), and cell division cycle 42 (Cdc42), and in synergy with TGF-β signaling can promote EMT inducing a decrease of E-cadherin expression and an increase of vimentin expression (Figure 3) [40, 77, 78] It seems that KRAS mutation alone is not able to modify the epithelial morphology of CRC cells but requires the cooperation of growth factor cues to accomplish the cell transformation. Neurothropic tyrosine receptor kinase B (TrkB) is a potent anoikis suppressor, which is overexpressed in tumor buds and in TABLE 1 | Studies which investigated the KRAS status and/or TB in relation to cell morphology and/or cellular plasticity, considered as EMT, or partial-EMT phenotype

Results

CONCLUSION

Findings

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