Implications for Tumor Microenvironment and Epithelial Crosstalk in the Management of Gastrointestinal Cancers

Abstract

Rapid advances in technology are revealing previously unknown organization, cooperation, and limitations within the population of nontumor cells surrounding the tumor epithelium known as the tumor microenvironment (TME). Nowhere are these findings more pertinent than in the gastrointestinal (GI) tract where exquisite cell specialization supports a complex microenvironmental niche characterized by rapid stemness-associated cell turnover, pathogen sensing, epithelial orchestration of immune signaling, and other facets that maintain the complex balance between homeostasis, inflammation, and disease. Here, we summarize and discuss select emerging concepts in the precancerous microenvironment, TME, and tumor epithelial-TME crosstalk as well as their implications for the management of GI cancers.

Figure 1

Inflammation and tissue restitution have complex implications for the gastrointestinal microenvironment. (a) The GI epithelium is exposed to a variety of inflammatory agents including bacteria, viruses, parasites, chemicals, and other components which promote injurious shifts in microbial populations and/or directly and (b) induce reactive oxygen and nitrogen species leading to epithelial DNA damage and mutations. Following DNA damage, (c) certain cell types escape DNA repair mechanisms, maintaining these somatic mutations (red), while (d) other cells with effectual DNA repair mechanisms, undergo apoptosis. (e) Macrophages (pink) recruited to the site of injury can engulf pathogens, as well as apoptotic epithelial cell bodies destroyed during inflammation. Macrophage-based detection of signal combinations indicating successful clearance of pathogens (e.g., IL-4 + apoptotic phosphatidyl-serine functional group) can induce (f) macrophage polarization and alternative activation and subsequent anti-inflammatory signaling. (g) Exposure to this signaling may promote tumorigenesis and/or progression in susceptible epithelial cells harboring mutations C or other sources, leading to establishment of tumors and/or metastatic transformation.

Figure 2

Metastasis and therapeutic efficacy are dictated by complexity within the tumor microenvironment. (a) The TME is comprised of an interacting landscape of unique cell types including tumor epithelia, tumor-associated macrophages, infiltrating T-cells, endothelial cells and pericytes, neurons, and cancer-associated fibroblasts. (b) In metastatic transformation, the TME programs tumor epithelia via EMT, cell fusion, and other processes leading to local invasion and dissemination to distant sites via CTCs and/or CTC clusters. (c) Metastatic dissemination is nonrandom, as in colon cancer where liver metastases are common, although the rules governing this remain to be fully understood. (d) Clinical and developmental drug therapies target or show preference for specific TME components, which factors into their efficacy in various tumor subtypes and combination therapy.