Cancer prevention and therapy through the modulation of the tumor microenvironment

Abstract

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.

Keywords: Cancer biology; Cancer prevention; Cancer therapy; Tumor microenvironment.

Figure 1. Targets and approaches identified that could modulate the tumor microenvironment to prevent or treat cancer

Key therapeutic targets identified include the inhibition of cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, IDO regulation of DCs, VEGF regulation of angiogenesis, fibrosis inhibition, endoglin, and JAK signaling. Potential therapeutic targets that have been identified and cross-validated, include many natural products including berberine, resveratrol, onionin A, EGCG, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone. These may warrant investigation as agents alone or in combination that target the tumor microenvironment for the treatment and prevention of cancer, although the specific target-approach combination as presented is not unique and other possibilities do exist.

Figure 2. The structures of natural products identified that may target the tumor microenvironment for the treatment or prevention of cancer

Molecules shown include berberine, resveratrol, onionin A, EGCG, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone.