Molecular pathways: involving microenvironment damage responses in cancer therapy resistance.

The armamentarium of therapeutics used to treat cancer patients relies heavily on ionizing radiation and chemotherapeutic drugs that severely damage DNA. Tumor cells' responses to such treatments are heavily influenced by their environment: Physical contacts with structural elements such as the extracellular matrix, associations with resident and transitory benign cells such as fibroblasts and leukocytes, and interactions with numerous soluble endocrine and paracrine-acting factors all modulate tumor-cell behavior. Of importance, this complex tumor microenvironment is not static and dynamically responds to a variety of stimuli. Here, we describe emerging data indicating that genotoxic cancer treatments activate highly conserved damage response programs in benign constituents of the tumor microenvironment. These damage signals, transmitted via master regulators such as NF-κB, culminate in a powerful and diverse secretory program that generates a proangiogenic, proinflammatory microenvironment. Constituents of this program include interleukin (IL)-6, IL-8, hepatocyte growth factor, amphiregulin, matrix metalloproteinases, and other factors that have been shown to promote adverse tumor-cell phenotypes, such as enhanced resistance to treatment and rapid tumor repopulation. A detailed understanding of these survival signals induced in the context of genotoxic stress provides a platform for developing combinatorial treatment strategies that take into account malignant cells, the tumor microenvironment, and the dynamics exerted by the treatment itself.