Role of tissue microenvironment resident adipocytes in colon cancer

Abstract

Colorectal cancer (CRC) is a multifactorial disease characterized by several genetic and epigenetic alterations occurring in epithelial cells. It is increasingly recognized that tumour progression is also regulated by tumour microenvironment (TME). The bidirectional cross-talk between tumour resident adipocytes and cancer cells within TME has been proposed as active contributor to carcinogenesis. Tumour resident adipocytes exhibit an activated phenotype characterized by increased secretion of pro-tumorigenic factors (angiogenic/inflammatory/immune) which contribute to cancer cell proliferation, invasion, neoangiogenesis, evasion of immune surveillance and therapy resistance. Furthermore, adipocytes represent a fuel rich source for increasing energy demand of rapidly proliferating tumour cells. Interestingly, a relationship between obesity and molecular variants in CRC has recently been identified. Whether adipose tissue promotes cancer progression in subsets of molecular phenotypes or whether local tissue adipocytes are involved in inactivation of tumour suppressor genes and/or activation of oncogenes still needs to be explored. This editorial highlights the major findings related to cross-talk between adipocytes and colon cancer cells and how local paracrine interactions may promote cancer progression. Furthermore, we provide future strategies in studying colonic TME which could provide insights in bidirectional cross-talk mechanisms between adipocytes and colonic epithelial cells. This could enable to decipher critical signalling pathways of both early colonic carcinogenesis and cancer progression.

Keywords: Adipose tissue; Cancer cell-tumour resident adipocyte cross-talk; Colon cancer microenvironment; Dysfunctional adipocytes; Tumour resident adipocytes.

Figure 1

Signalling pathways activated by tumour resident adipocytes secreted factors. Tumour resident adipocytes secreted factors activate cell cycle regulators and inflammatory/immune/angiogenic regulators. Cancer cell secreted inflammatory cytokines activate host cells of TME constituting a paracrine/autocrine loop. MAPK: Mitogen-activated protein kinases; PI3K: Phosphoinositide 3-kinase; AKT: Protein Kinase B; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor-κB; JAK/STAT3: Janus kinase/signal transducers and activators of transcription 3; HIF-1α: Hypoxia-inducible factor 1-alpha; TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin-6.

Figure 2

Colon cancer progression and tumour microenvironment. Bi-directional cross-talk between host cells of tumour microenvironment (TME) contributes to colon cancer progression. Activated tumour resident adipocytes increase secretion of cytokines, growth factors, adipokines and release lipid metabolites promoting colon cancer cell proliferation and migration. Cancer cells secrete inflammatory factors which repopulate TME, further enhancing cancer cell proliferation. Tis: carcinoma in situ; T1: Tumour invades submucosa; T2: Tumour invades muscularis propria; T3: Tumour invades through muscularis propria into pericolorectal tissues; T4a: Tumour penetrates to the surface of the visceral peritoneum; T4b: Tumour directly invades or is adherent to other organs or structures.

Figure 3

Paracrine interactions between dysfunctional adipose tissue, colon cancer cells and normal epithelial cells. Dysfunctional adipose tissue induces recruitment of macrophages and lymphocytes creating a favourable microenvironment for tumour initiation and progression. We propose that dysfunctional adipocytes may induce epigenetic mutations in neighbouring epithelial cells. Adipocyte activation and recruitment signals from colon cancer cells are not known.