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.

Advanced Molecular Science Research Centre King George's Medical University Lucknow Uttar Pradesh India

Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD United States

Charles University Prague 3rd Faculty of Medicine Prague Czech Republic

Department of Biology Southern Connecticut State University New Haven CT United States

Department of Biology University of Rome Tor Vergata Rome Italy

Department of Biomedical Sciences Ohio University Athens OH United States

Department of Biomedical Sciences School of Medicine Creighton University Omaha NE United States

Department of Clinical Pharmacy and Therapeutics Applied Science University Amman Jordan

Department of Comparative Pathobiology Purdue University Center for Cancer Research West Lafayette IN United States

Department of Environmental Sciences Faculty of Agriculture Dalhousie University Nova Scotia Canada

Department of Experimental and Clinical Medicine University of Florence Florence Italy

Department of Oncology Wayne State University School of Medicine Detroit MI United States

Department of Orthopedic Surgery Nara Medical University Kashihara Japan

Division of Oncology Departments of Medicine and Pathology Stanford University School of Medicine Stanford CA United States

Division of Urology Sunnybrook Health Sciences Centre Toronto Ontario Canada

Institute of Cancer Sciences University of Glasgow Glasgow United Kingdom

Medical Scientist Training Program Mayo Graduate School Mayo Medical School Mayo Clinic Rochester MN United States

Mount Sinai Roosevelt Hospital Icahn Mount Sinai School of Medicine New York City NY United States

New York Medical College Valhalla NY United States

Ovarian and Prostate Cancer Research Laboratory Guildford Surrey United Kingdom

Physics Department School of Applied Mathematics and Physical Sciences National Technical University of Athens Athens Greece

Sanus Biosciences San Diego United States

School of Chemical and Biotechnology SASTRA University Thanjavur 613401 Tamil Nadu India

University of Florence Florence Italy

University of Illinois at Urbana Champaign Champaign Urbana IL United States

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