Abstract 3429: Promotion of metastasis by frequently used chemotherapeutic agents
Authors: Daenen Laura G. , Roodhart Jeanine M.L. , Voest Emile E. 
Published: February 2011

It is commonly assumed that early cancer progression during chemotherapy is part of the natural course of disease. However, there is increasing evidence that chemotherapy, in addition to its cytotoxic effects, may also confer tumor-favorable signals as part of a host response. Prime examples are increases in circulating, pro-angiogenic endothelial progenitor cells (EPCs) and growth factors after chemotherapy. We hypothesize that when tumors can overcome the cytotoxic effects of chemotherapy through resistance, these tumor-favorable signals will obfuscate the benefits of treatment and may actually facilitate metastatic spread.

In order to study therapy-induced metastasis formation in absence of direct cytotoxic effects on tumor cells, mice were pre-treated with chemotherapy. Four days later, when the cytotoxic agents had been cleared from circulation, tumor cells were injected intravenously. Thirteen days after tumor cell injection, lung metastases had formed in untreated mice (5.4±3.9 surface metastases). Remarkably, pre-treatment with two chemotherapeutic agents that are frequently used in clinical practice, paclitaxel and cisplatin, showed a robust increase in the number of lung colonies compared to untreated mice (12.7±6.9, p=0.0003 for paclitaxel and 32.7±9.9, p&lt;0.0001 for cisplatin). Similar effects were observed when using a different tumor cell line in a second mouse strain. Additional experiments in immune deficient Rag2−/−γc−/− mice showed that suppression of the immune system by chemotherapy does not account for this effect, as chemotherapy still enhanced metastasis formation in these mice (5.5±4.0 surface metastases in untreated mice compared to 28.3±11.8 in cisplatin pre-treated mice, p=0.01). Nevertheless, combining chemotherapy with antibodies against the murine vascular endothelial growth factor receptor 2 (VEGFR2) fully abrogated the chemotherapy-induced increase in metastases (3.0±3.7, p=0.0004 compared to chemotherapy alone). This implies that chemotherapy has the ability to signal through the VEGFR2 pathway to promote metastasis. Whether this is due to local pro-angiogenic effects in the lungs, or to a systemic mobilization of VEGFR2-expressing EPCs into the circulation, is currently under investigation.

In conclusion, we show that two widely used chemotherapeutic drugs, with different mechanisms of action, are able to increase metastasis formation when direct cytotoxic effects on tumor cells are absent. Targeting VEGFR2 interferes with the enhanced metastatic pattern. These data provide novel evidence for interactions between chemotherapy and the microenvironment, which could potentially lead to early progression in patients with chemoresistant tumors.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3429.