Systematic review of the old and new concepts in the epithelial-mesenchymal transition of colorectal cancer

Abstract

Epithelial-to-mesenchymal transition (EMT) is defined as the transformation of an epithelial cell into a spindle cell with the loss of membrane E-cadherin expression and the gain of mesenchymal markers positivity. In the field of colorectal cancer (CRC), first data about EMT was published in 1995 and more than 400 papers had been written up to March 2016. Most of them are focused on the molecular pathways and experimentally-proved chemoresistance. In the present article, an update in the field of EMT in CRC based on the review of the literature and personal experience of the authors is presented. The information about the molecular and immunohistochemical (IHC) particularities of these processes and their possible role in the prognosis of CRC were also up-dated. This article focuses on the IHC quantification of the EMT, the immunoprofile of tumor buds and on the relation between EMT, angiogenesis, and stem cells activation. The EMT-induced chemoresistance vs chemotherapy- or radiotherapy-induced EMT and cellular senescence was also synthesized for both conventional and targeted therapy. As a future perspective, the EMT-angiogenesis-stemness link could be used as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management of patients with CRC. Association of dexamethasone and angiotensin converting enzyme inhibitors combined with conventional chemotherapies could have clinical benefits in patients with CRC. The main conclusion is that, although many studies have been published, the EMT features are still incompletely elucidated and newly discovered EMT markers provide confusing data in understanding this complicated process, which might have significant clinical impact.

Keywords: Angiogenesis; Budding; Chemoresistance; Colorectal cancer; Epithelial-mesenchymal transition.

Figure 1

Preferred reported items for systematic reviews and meta-analyses (PRISMA) flow diagram adapted for data about epithelial mesenchymal transition in colorectal cancer in the PubMed database between 1995 and 2016 (First of March).

Figure 2

Epithelial mesenchymal transition-related immunoprofile of buds of colorectal cancer. β-catenin displays cytoplasmic (A) or membrane positivity in the tumor core (B) with nuclear switch in buds (C), whereas membrane E-cadherin expression (D) is lost in the invasion front (E).

Figure 3

Nuclear positivity for Slug (A), and cytoplasmic expression of vascular endothelial growth factor-A (B) in the colorectal cancer cells.

Figure 4

Immunoexpression of the epithelial mesenchymal transition-related markers in primary tumor (A, C, E) vs hepatic metastases (B, D, F). Membrane positivity for E-cadherin (A, B) and β-catenin (C, D), and negativity for N-cadherin (E, F) with positive neural structures (arrows). The normal hepatocytes express E-cadherin (B), β-catenin (D), and N-cadherin (F).

Figure 5

Molecular pathways of epithelial mesenchymal transition in colorectal cancer cells. EMT: Epithelial mesenchymal transition; CRC: Colorectal cancer; hTERT: Human telomerase reverse transcriptase; TGF-β: Transforming growth factor-beta.