Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewFriend or foe?: The tumour microenvironment dilemma in colorectal cancer
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
Transparency document
Conflict of interest
The Authors declare that they have no conflicts of interest.
References (169)
- et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
A genetic model for colorectal tumorigenesis
Cell
(1990) - et al.
Colorectal cancer
Lancet
(2010) - et al.
CIMP, at last
Gastroenterology
(2005) - et al.
Genomic correlates of immune-cell infiltrates in colorectal carcinoma
Cell Rep.
(2016) - et al.
CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis
Cell Stem Cell
(2014) - et al.
Identification of colonic fibroblast secretomes reveals secretory factors regulating colon cancer cell proliferation
J. Proteome
(2014) - et al.
New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape
Curr. Opin. Immunol.
(2014) - et al.
IgE, mast cells, basophils, and eosinophils
J. Allergy Clin. Immunol.
(2010) - et al.
Tumor eosinophil infiltration and improved survival of colorectal cancer patients: Iowa Women's Health Study
Mod. Pathol.
(2016)
Development and function of dendritic cell subsets
Immunity
Dendritic cells and cytokines in human inflammatory and autoimmune diseases
Cytokine Growth Factor Rev.
Natural killer cells infiltrating colorectal cancer and MHC class I expression
Mol. Immunol.
Receptors and signaling mechanisms for B-lymphocyte activation, proliferation and differentiation—insights from both in vivo and in vitro approaches
FEBS Lett.
Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments
Blood
The functional and prognostic implications of regulatory T cells in colorectal carcinoma
J. Gastrointest. Oncol.
Microenvironmental regulation of tumor progression and metastasis
Nat. Med.
Molecular genetics of colorectal cancer
Annu. Rev. Pathol.
New insights into the aetiology of colorectal cancer from genome-wide association studies
Nat. Rev. Genet.
Molecular origins of cancer: molecular basis of colorectal cancer
N. Engl. J. Med.
Microsatellite instability in colorectal cancer
Gastroenterology
Molecular origins of cancer: epigenetics in cancer
N. Engl. J. Med.
Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina associated domains
Nat. Genet.
Chromosomal instability and cancer: not just one CINgle mechanism
Gut
Stromal gene expression defines poor-prognosis subtypes in colorectal cancer
Nat. Genet.
Stromal contribution to the colorectal cancer transcriptome
Nat. Genet.
The consensus molecular subtypes of colorectal cancer
Nat. Med.
Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy
Clin. Cancer Res.
Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue
Mol. Cancer Res.
Cancer associated fibroblasts: the dark side of the coin
Am. J. Cancer Res.
Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts
Oncogene
Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A
J. Exp. Med.
Carcinoma-associated fibroblasts: orchestrating the composition of malignancy
Genes Dev.
Tumour-associated fibroblasts and mesenchymal stem cells: more similarities than differences
J. Cell. Mol. Med.
Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment
Front. Oncol.
Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature
Clin. Cancer Res.
A monotonic and prognostic genomic signature from fibroblasts for colorectal cancer initiation, progression, and metastasis
Mol. Cancer Res.
A 5-gene classifier from the carcinoma-associated fibroblast transcriptomic profile and clinical outcome in colorectal cancer
Oncotarget
Cancer immunoediting: from immunosurveillance to tumor escape
Nat. Immunol.
Paradoxical roles of the immune system during cancer development
Nat. Rev. Cancer
The inflammatory tumor microenvironment and its impact on cancer development
Contrib. Microbiol.
Possible biological and translational significance of mast cells density in colorectal cancer
World J. Gastroenterol.
A protective role of mast cells in intestinal tumorigenesis
Carcinogenesis
High density of tryptase-positive mast cells in human colorectal cancer: a poor prognostic factor related to protease-activated receptor 2 expression
J. Cell. Mol. Med.
High infiltration of mast cells positive to tryptase predicts worse outcome following resection of colorectal liver metastases
BMC Cancer
Neutrophil recruitment and function in health and inflammation
Nat. Rev. Immunol.
Distinct functions of neutrophil in cancer and its regulation
Mediat. Inflamm.
The tumor microenvironment in colorectal carcinogenesis
Cancer Microenviron.
Gradient infiltration of neutrophil extracellular traps in colon cancer and evidence for their involvement in tumour growth
PLoS One
Systemic neutrophil-to-lymphocyte ratio in colorectal cancer: the relationship to patient survival, tumour biology and local lymphocytic response to tumour
Br. J. Cancer
Cited by (62)
AQP9 transports lactate in tumor-associated macrophages to stimulate an M2-like polarization that promotes colon cancer progression
2022, Biochemistry and Biophysics ReportsColon cancer patients with mismatch repair deficiency are more likely to present as acute surgical cases
2021, European Journal of CancerCitation Excerpt :The relationship between MMR status of the tumour and risk for acute surgery for CC was apparently not by chance because this association was seen in two cohorts differing in origin and time of surgery. This observation may originate from a relationship between tumour cell biology and the tumour microenvironment that we do not fully understand [43]. As previous studies have shown, tumours with dMMR status accumulate many mutations, which can give rise to frameshift peptide neoantigens.
Tumor-on-chip modeling of organ-specific cancer and metastasis
2021, Advanced Drug Delivery ReviewsAdvances on colorectal cancer 3D models: The needed translational technology for nanomedicine screening
2021, Advanced Drug Delivery ReviewsCitation Excerpt :As consequence, less than 10% of novel anticancer drug candidates in clinical trials are eventually approved by FDA [8]. This major gap in the translation of preclinical breakthroughs to the market results essentially from the unmet need of having preclinical models that better resemble the tumor microenvironment (TME) [9,10], where genetic cues [11], as well as physical and mechanical properties [12] contribute to disease development, metastatic spread and response to therapy [13]. Most of our knowledge about cancer biology, signaling pathways and therapeutic targets has been provided by two-dimensional (2D) systems with immortalized cancer cell lines, however it is now well accepted their substantial limitations for testing new drugs [14].
Bacterial lipopolysaccharide modulates immune response in the colorectal tumor microenvironment
2023, npj Biofilms and MicrobiomesEndoplasmic reticulum stress mediates the myeloid-derived immune suppression associated with cancer and infectious disease
2023, Journal of Translational Medicine
- 1
These two authors equally contributed to the work.