Host-Mediated Mechanisms of Resistance to Antitumor Therapies

Abstract

In addition to their direct effects on tumor cells, certain anticancer therapies elicit a prosurvival response in benign tissues in the tumor microenvironment. This host response can be seen as an attempt of the body to diminish chemotherapy-induced damage in tissues crucial for functioning. Unfortunately, this acute reaction to damage can be exploited by the tumor to reduce therapy-induced damage in cancer cells. The host response can therefore interfere with the antitumor activity of a drug, and may provide an explanation for the limited success of certain anticancer agents. Targeting the host response will likely augment current antitumor therapies. In this thesis we have utilized preclinical and translational studies to show that the host response following chemotherapy exposure consists of changes in numerous cell types and cytokines. For example, we show that chemotherapy can activate cells in the pulmonary vascular bed to create a favorable niche for tumor cell colonization, a process involving upregulation of VEGFR-1 on pulmonary endothelial cells. When chemotherapy was combined with antibodies targeting VEGFR-1, this effect was reversed and the number of lung colonies was decreased. Furthermore, platinum-containing chemotherapeutics induce a host response in mesenchymal stem cells, leading to secretion of rare fatty acids (PIFAs) that can protect tumors against a broad spectrum of chemotherapeutic drugs. Inhibitors of COX-1 and thromboxane synthase could prevent PIFA formation. Addition of either of these inhibitors to chemotherapy blocked the release of PIFAs from MSCs, ameliorating the antitumor effects of the cytotoxic agent. Interestingly, these same PIFAs are found in fish oil, which can induce resistance to chemotherapy in mouse models as well. In healthy volunteers, rapid rises in PIFA plasma levels were found after intake of the recommended daily amount of fish oil. Our findings show that fish oil might not be just an innocent food supplement during chemotherapy. Acute responses of host tissues to antitumor agents are not exclusive to chemotherapy. A similar host response takes place after administration of ‘cytotoxic-like’ vascular disrupting agents (VDAs) in mice and men. Mobilization of pro-tumorigenic bone marrow-derived cells into the circulation has been shown, which promotes angiogenesis and indirectly also tumor growth. When the mobilization of these bone marrow-derived cells was blocked by co-administration of an agent targeting VEGFR-2 present on their cell membranes, tumor regrowth was prevented, resulting in enhanced tumor control. All of these factors may interfere with the antitumor activities of the drugs. The net effect of antitumor therapy will thus be determined by both the direct antitumor effects, as well as by the counteracting host response. Based on our preclinical results, combining conventional chemotherapy with agents blocking specific aspects of the systemic host response seems promising to enhance chemotherapy efficacy. By improving our understanding of the prosurvival effects of chemotherapy on the microenvironment, we aim to provide novel strategies to optimize antitumor therapy. Therefore, this thesis is an incentive to combine conventional antitumor therapies with novel ‘targeted agents’, and to develop new drugs targeting the tumor microenvironment.