|M.Sc Student||Bril Rotem|
|Subject||The Response to Radiotherapy May Induce Metastasis in Mice|
|Department||Department of Medicine||Supervisor||PROF. Yuval Shaked|
|Full Thesis text|
One of the major obstacles in cancer treatment is that tumors eventually develop resistance to therapy, and as a result they relapse and/or metastasize. Our previous studies show that systemic administration of several cytotoxic drugs can induce factors produced by the host which contribute to tumor angiogenesis and subsequent tumor re-growth. Thus, anti-cancer drug therapy, in addition to its therapeutic benefits, may also possess pro-tumorigenic effects. However, potential pro-tumorigenic effects generated by the host in response to local radiation have yet to be revealed. Using several in vivo and in vitro assays on colorectal cancer cells and endothelial cells we evaluated the angiogenesis and metastasis properties of tumors following a single dose of local radiation. Our results show that such a therapy can induce mobilization of bone marrow derived cells known to contribute to tumor angiogenesis. These cells were found in large numbers in Matrigel plugs which contained plasma obtained from non-tumor bearing mice after they were exposed to local radiation. However, such cells were not found in Matrigel plugs which contained plasma from control untreated mice. In addition, mice irradiated locally with a single dose of irradiation and subsequently were injected via the tail vein with colon cancer cells succumb to metastases prior to their control non-irradiated mice. Moreover, colon cancer cells exposed to plasma from locally irradiated mice were found to be more aggressive by means of invasive than colon cancer cells exposed to plasma from control mice. In order to screen for the possible mechanism(s) involved in host pro-metastatic effects following radiation, screening assays were conducted in which we focused on various inflammatory and angiogenic factors. The results of such an assay revealed that the host factor, interferon gamma induced protein 10 (IP-10), was markedly upregulated in the bone marrow condition medium of mice, following local radiation. Furthermore, IP-10 has been recently demonstrated to induce invasion and migration properties of colorectal cancer cells, and hence may serve as a potential biomarker for radiation based-therapy outcome.
Overall, our results indicate that local radiation in addition to its undoubted clinical benefit in shrinking tumors, it may also induce host effects which in turn possess pro-tumorigenic and pro-metastatic properties, and therefore may decrease the therapy outcome. Additional per-clinical and clinical studies are required in order to identify whether such reported possible pro-tumorigenic effects found in mice are relevant to cancer patients following radiotherapy.