Abstract
Chemotherapy is the main treatment modality for patients with metastatic disease. Unfortunately, response to chemotherapy is only transient and eventually almost all tumors become resistant to chemotherapy. Development of resistance to chemotherapy is therefore one of the major obstacles in the effective treatment of cancer patients with metastatic disease. In
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addition to conventional chemotherapy, more and more targeted therapies are directed against specific properties of the tumor cell itself, against the cells in the immediate vicinity of the tumor or to certain growth factors that are known to stimulate tumor growth. This thesis focuses on the tumor-host interaction, it examines the role of different bone marrow derived cells (BMDCs) in tumor growth, metastasis formation and response to therapy in order to find new targets to improve anti-cancer therapy in patients. The clinical implications of this thesis mainly consist of optimizing the effect of current treatments by better combining agents and identifying new targets for therapy. Based on our results, combining conventional chemotherapy with targeted therapies, in order to prevent the systemic host-repair response, seems promising to enhance chemotherapy efficacy. Various combinations with agents targeting the different aspects of the tumor-host interaction could be explored. Conventional chemotherapy can potentially be combined with agents targeting the various growth factors and cytokines involved in the release or homing of BMDC to the tumor, including VEGF and SDF1α. Secondly, agents blocking the downstream effects of the BMDCs, including inhibition of the production of the identified PIFAs as described in chapter 2 and antibodies against e.g. Il-6, CCL5, VEGFR-1, can potentially enhance the efficacy of chemotherapy. Thirdly, more general modulators of the micro-environment like erlotinib, imatinib or hedgehog inhibitors are promising targets to enhance conventional chemotherapy. Notably, besides choosing the right combination of drugs, the timing of the different drugs is also essential to optimize efficacy by preventing the chemotherapy-induced host response in time. In the design of new clinical studies, this concept of enhancing conventional chemotherapy by blunting the host-repair response should be further explored. Concluding, this thesis shows that in addition to the direct anti-tumor effect of the chemotherapy, chemotherapy elicits a protective host response that actually promotes tumor growth. The outcome will therefore be determined by the balance between the cytotoxic effects of chemotherapy on one hand versus the activation of the microenvironment on the other hand, which might obfuscate the benefits of treatment and may actually induce resistance. Clinical studies are needed to evaluate the relative importance of this mechanism in the treatment of patients with cancer
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