Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor

Agents that inhibit vascular endothelial growth factor (VEGF) signaling are increasingly incorporated into treatment regimens for metastatic human cancer, yet the overall benefit of this treatment strategy has been relatively modest [1,2]. Both clinical and experimental studies indicate that many or most malignancies will ultimately progress if VEGF blockade is sustained, and that progression may involve both progressive primary tumor growth and enhanced metastasis. The mechanisms for acquired resistance to this treatment approach are thus of great interest, but are still emerging. We previously found that VEGF inhibition significantly reduced primary tumor growth and the incidence of spontaneous lung metastasis in the orthotopic renal SKNEP1 tumor model over a six week treatment period, and regressed established metastases in late-stage tumors [3,4]. Recent findings, however, indicate that disruption of VEGF signaling and consequent tumor hypoxia may ultimately promote invasion and metastasis in several tumor models [5,6], overcoming the initial anti-metastatic effects of limiting angiogenesis. Prior studies suggest that hypoxia-regulated and proinflammatory genes expressed by tumor cells and stroma, such as COX-2, can promote the establishment of metastatic deposits in the lung. For example, Massague and coworkers previously found that COX-2 and other genes involved in vascular remodeling, identified as components in a "lung metastasis gene signature", functioned collectively to promote metastasis in a breast cancer model [7,8]. More broadly, much recent data supports a role for systemic inflammation in the promotion of metastasis in general [9], including dissemination to the lung [10]. For example, mice genetically prone to autoimmune arthritis are significantly more prone to develop lung metastasis than nonarthritic controls [11]. Recruitment of COX-2-expressing macrophages can create an inflammatory proangiogenic environment that strongly promotes tumor growth