Countering chemo-induced metastasis
Michael J. Haas
2011
Science-Business eXchange
Two independent research teams have elucidated mechanisms by which cisplatin and paclitaxel can promote lung metastases in mice, providing links between the chemotherapies and the known metastatic effects of upregulating VEGF receptor 1 and matrix metalloproteinase 9, which acts downstream of the receptor. 1, 2 The findings could create additional uses for inhibitors of VEGF receptor 1 (FLT1; VEGFR-1) and revive work on matrix metalloproteinase (MMP) inhibitors, a class of beleaguered cancer
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... pounds that has all but disappeared from development. Multiple preclinical studies have shown that chemotherapy can promote metastatic tumor growth, 3-5 and a handful of clinical trials have suggested chemotherapy can accelerate the growth of cancer cells. 6, 7 In the past five years, researchers have shown that chemotherapy can increase levels of circulating endothelial progenitor cells that contribute to tumor regrowth and angiogenesis, 8, 9 and they have shown that these progenitor cells correlated with tumor progression and poor survival in patients. 10 Despite the known link, the molecular mechanisms underlying chemotherapy's tumorigenic and prometastatic effects remained unclear. Part of the reason was that most studies had tracked the drugs' tumor-promoting effects in animals that already had tumors. This made it difficult to tease apart the specific mechanisms of druginduced tumor growth from the drug's tumor-killing cytotoxicity. To isolate the effects of chemotherapy on metastatic tumor growth, a team from University Medical Center Utrecht and, independently, an Israeli-Italian group both used an approach whereby they treated normal mice with a chemotherapeutic, allowed the drug to clear from circulation and then injected the mice with tumor cell lines. The stepwise process permitted the teams to model what happens in patients whose primary tumors have been decreased to undetectable levels by chemotherapy but who have aggressive or metastatic tumor cells in circulation. The UMC Utrecht group pretreated mice with cisplatin and injected the animals with colon cancer or melanoma cell lines. Those animals developed more lung metastases than control mice pretreated with vehicle. The team also found higher expression of Veg fr-1 on lung endothelial cells in cisplatin-pretreated mice than on endothelial cells in other organs or on cells from vehicle-pretreated controls. In mice injected with the cancer cell lines, pretreatment with cisplatin and an antibody against Vegfr-1 resulted in fewer lung metastases than pretreatment with cisplatin, the antibody or vehicle monotherapy. Collectively, the findings showed that chemotherapy can promote the growth of metastatic tumors by upregulating VEGFR-1 on endothelial cells, thus providing a rationale for adding VEGFR-1 inhibitors to chemotherapy regimens, the team wrote in its Cancer Research report. The team leader was Emile Voest, head of the department of medical oncology at UMC Utrecht. The two most advanced VEGFR-1 inhibitors are Votrient pazopanib and axitinib. Votrient, a broad-spectrum inhibitor of VEGFR-1 and other tyrosine kinases from GlaxoSmithKline plc, is approved to treat renal cancer and in Phase III testing to treat ovarian and breast cancers and sarcoma. Axitinib (AG-013736), an inhibitor of VEGFR-1, VEGFR-2 (KDR/ Flk-1) and VEGFR-3 (FLT4) from Pfizer Inc., is in registration to treat renal cancer and Phase II testing to treat breast, gastrointestinal, lung and thyroid cancers. Enter the matrix Concurrent to the Dutch team's work, researchers from Technion-Israel Institute of Technology, Emek Medical Center and the European Institute of Oncology began to connect the dots between chemotherapy, tumor metastasis and MMP9 expression on bone marrow-derived cells. The Israeli-Italian team took note of other groups' preclinical studies showing that mouse bone marrow-derived cells expressing Vegfr-1 contributed to tumor metastasis 11 and that MMP9 contributed to tumorigenesis. 12 Taken together with its own studies of the role of bone marrow-derived cells in tumor regrowth, 8,9 the team hypothesized that chemotherapy induced MMP9 expression on those cells to promote metastatic tumor growth. To investigate this hypothesis, first the researchers collected plasma and bone marrow-derived cells from normal mice treated with paclitaxel or vehicle. Plasma from paclitaxel-treated mice increased the in vitro migration and invasive activity of a normal human endothelial cell line, two human breast cancer cell lines and two mouse cancer cell lines compared with plasma from vehicle-treated controls. The team also found that plasma from paclitaxel-treated mice increased MMP9 expression in a human breast cancer cell line. Moreover, bone marrow-derived cells from those mice expressed higher levels of Mmp9 than cells from vehicle-treated mice. In mice pretreated with paclitaxel, compared with vehiclepretreated controls, a lung carcinoma cell line increased the number of lung metastases and decreased survival. Pretreatment with paclitaxel and an MMP9 inhibitor reduced lung metastases and improved survival compared with pretreatment using paclitaxel monotherapy. Data were published in Cancer Research. Collectively, the findings suggest chemotherapy may have protumorigenic side effects that upregulate host factors such as
doi:10.1038/scibx.2011.1226
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