Molecular Pathways: Targeting the Microenvironment of Liver Metastases

Abstract

Curative treatment for metastatic solid cancers remains elusive. The liver, which is nourished by a rich blood supply from both the arterial and portal venous systems, is the most common site of visceral metastases, particularly from cancers arising in the gastrointestinal tract, with colorectal cancer being the predominant primary site in Western countries. A mounting body of evidence suggests that the liver microenvironment (LME) provides autocrine and paracrine signals originating from both parenchymal and nonparenchymal cells that collectively create both pre- and prometastatic niches for the development of hepatic metastases. These resident cells and their molecular mediators represent potential therapeutic targets for the prevention and/or treatment of liver metastases (LM). This review summarizes: (i) the current therapeutic options for treating LM, with a particular focus on colorectal cancer LM; (ii) the role of the LME in LM at each of its phases; (iii) potential targets in the LME identified through preclinical and clinical investigations; and (iv) potential therapeutic approaches for targeting elements of the LME before and/or after the onset of LM as the basis for future clinical trials. Clin Cancer Res; 23(21); 6390-9. ©2017 AACR.

Figure 1. Cell-cell interactions in the liver microenvironment

Shown is a diagrammatic representation of the interactions between the cancer cells the various hepatic cell types that regulate progression of metastasis and the soluble factors mediating these interactions. Green arrows represent interactions that favor metastatic expansion, red arrows represent interactions that are detrimental to cancer cell growth and blunt-end yellow arrows indicate interactions that impede anti-tumor immunity.

Figure 2. Stromal and immune cells of the liver microenvironment and their contribution to progression of metastasis

Listed are the cells constituting the hepatic microenvironment and their tumor-promoting contributions in each phase of the metastatic process. Also listed are potential therapeutic strategies aimed at inhibiting pro-tumorigenic stromal cell functions and inflammatory responses.