Review
Friend or foe?: The tumour microenvironment dilemma in colorectal cancer

https://doi.org/10.1016/j.bbcan.2016.11.001Get rights and content

Abstract

The network of bidirectional homotypic and heterotypic interactions established among parenchymal tumour cells and surrounding mesenchymal stromal cells generates the tumour microenvironment (TME). These intricate crosstalks elicit both beneficial and adverse effects on tumour initiation and progression unbalancing the signals and responses from the neighbouring cells.

Here, we highlight the structure, activities and evolution of TME cells considering a novel colorectal cancer (CRC) classification based on differential stromal composition and gene expression profiles. In this scenario, we scrutinise the molecular pathways that either change or become corrupted during CRC development and their relative prognostic value.

Finally, we survey the therapeutic molecules directed against TME components currently available in clinical trials as well as those with stronger potential in preclinical studies. Elucidation of dynamic variations in the CRC TME cell composition and their relative contribution could provide novel diagnostic or prognostic biomarkers and allow more personalised therapeutic strategies.

Introduction

Cancer is a genetic disease that arises through a multistep process whereby somatic cells acquire and accumulate multiple genetic and epigenetic changes that result in unrestrained proliferation [1]. A tumour is no longer depicted as a collection of relatively homogeneous cancer cells, whose biology could be understood only by elucidating the properties of these autonomously growing cells. A cancer is now recognised, instead, as a complex tissue composed of multiple distinct cell types, mainly derived from the neighbouring mesenchymal stroma with which tumour cells establish the so-called “tumour microenvironment” (TME) [1]. The functional interactions between tumour and stromal cells sustain growth and invasion. Neoplastic cells, in fact, emit a series of signals that convert the adjacent microenvironment into a pathological entity that continually evolves during cancer progression; the resulting TME, in turn, appears to dictate aberrant tissue functions and to play a critical role in the development of more advanced and therapy-refractory malignancies [1], [2]. The orchestration of such events involves an array of cell types that contribute to the biology of tumours via individual and collective functions, greatly influencing disease initiation, progression and patient prognosis [2].

In this review, we define the biological landscape of the colorectal cancer (CRC) TME taking into account a recent CRC classification and highlighting the intricate network generated among the distinct cell types that participate in its construction. The functions that tumour parenchymal and stromal cells, specifically cancer-associated fibroblasts and immune cells, serve during the various steps of tumour progression are illustrated as well as mechanisms whereby conflicting signals may re-educate or corrupt single components culminating into a reshaped microenvironment that ultimately leads to a different outcome (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Table 1).

Section snippets

A new microenvironment-based CRC classification

CRC has provided a paradigm for studying tumourigenesis since the development of the Fearon-Vogelstein model [3], [4], [5]. CRC arises via clonal expansion of colonic crypt cells bearing loss-of-function mutations in APC or gain-of-function mutations in CTNNB1. These mutations foster the persistent activation of the Wnt pathway that regulates the stem cell compartment and cell fate along the crypt-villus axis. This results in β-catenin translocation to the nucleus and its interaction with

Cancer associated fibroblasts (CAF)

The stroma plays an essential role in tissue architecture, providing a physical support for the functions of residing cells [1]. In the normal colonic mucosa, fibroblasts are the major stromal population, spread throughout the lamina propria adjacent to the colon mucosal epithelium and are responsible for the synthesis, deposition and turnover of the basement membrane components. The crosstalk between these cells and the epithelial compartment contributes to tissue integrity that, if altered,

Cell-cell communications in the CRC microenvironment

The integrity of the intestinal wall is accomplished by intensive communications established among all cellular components. During carcinogenesis, the role that each cell plays is no longer fine-tuned so that the orchestration easily becomes dissonant, impairing tissue homeostasis and damaging the organism's health [111]. These communications are mediated by gap junction channels (GJs) and autocrine/paracrine mechanisms. These latter are made possible through the synthesis and secretion of

CRC microenvironment targeted therapy

The complex interplay of tumour cells with all components of the microenvironment in CRC has emerged as a critical aspect of tumour biology and is strongly associated with the host ability to control growth and respond to therapies [13], [17]. Most anticancer strategies in humans are designed to target the intrinsic properties of cancer cells resulting from their more variegated and mutated genotypes. Conventional treatments, however, frequently generate structural and functional alterations of

Conclusions and perspectives

In this review, we have drawn a picture of the complex scenario generated in the CRC microenvironment that involves many different players in line with the recently reported CRC subtype classification. Cancer cells and cancer stem cells still remain the leading actors while CAFs and immune cells are emerging as pivotal among mesenchymal stromal cells. We illustrated the intense crosstalk established among all cellular components that change intriguingly with time and the pathways that become

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Conflict of interest

The Authors declare that they have no conflicts of interest.

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