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The main research interest of the laboratory is the study of tumor-host interactions. There is growing evidence that the normal tissue co-opted and modified by the growing tumor, provide essential cues to tumor maintenance, dormancy, growth, invasion and metastasis. We are particularly interested in understanding how the growing tumor modify normal tissue to its advantage, how this modify tissue contribute to tumorigenesis and how therapeutic interventions modify this cross-talk, and what are the consequences. More specifically we are investigating the following aspects of tumor - host interaction:
Impact of angiogenesis and antiangiogenic therapies to tumor progression
Angiogenesis is thought to promote tumor growth though the delivery of oxygen and nutriments to the growing tumor, but evidence suggests that additional mechanisms may be involved. We are interested in unraveling paracrine effects of angiogenic vessels on primary tumor growth, tumor invasion and metastasis formation. One signaling pathways we are analyzing is the Akt/PKB pathway, which has potent angiogenic activity. Furthermore, while it has been traditionally assumed that antiangiogenic treatments will not face the problems of resistance as observed during chemotherapy, emerging evidence indicates that indeed tumors can escape angiogenic blockade. We are interested in identifying mechanisms of escape and new molecules as candidate therapeutic targets to prevent/treat escape.
Monitoring tumor angiogenesis
A main question and challenge in the field of clinical anti-angiogenesis research is how to improve the monitoring of antiangiogenic drugs tested in clinical trials. The efficacy of conventional anticancer agents is commonly evaluated by measuring their direct effect on tumor size (i.e. response rate), and ultimately survival (i.e. prolongation of time to progression and time to death). To assess an antiangiogenic effect the response rate is an inadequate endpoint. Since the antitumor effect of antiangiogenic drugs is indirect we need to be able to assess the biological effects on the tumor vasculature independently of the overall antitumor activity and clinical response. New surrogate markers of angiogenesis and/or antiangiogenic activity need to be identified and subsequently validated. Many approaches to quantify tumor angiogenesis in patients in a non-invasive and reliable manner are being considered and investigated. We are currently exploring cellular, biochemical and functional markers of angiogenesis in experimental cancer models and in cancer patients.
Contribution of bone marrow-derived cells to tumor progression and metastasis
Cells recruited to the tumor microenvironment, in particular BMDC and inflammatory cells, contribute to tumor progression, by establishing paracrine relationships with the tumor cells. In particular monocytes/macrophages, are important sensors of tissue hypoxia and necrosis. We are characterizing the mechanisms of mobilization of these cells, their contribution to local tumor growth and their role in generating premetastatic niches.
Inflammatory mechanisms of tumor promotion
Inflammation promotes tumor progression through various mechanisms including expression of COX-2 and prostaglandin production. COX-2 acts as tumor promoter by inducing angiogenesis and stimulating tumor cell survival and motility. We are interested in identifying downstream target genes of COX-2 and molecular mediators of its effects on endothelial cells and tumor cells.
Radiation-induced stroma remodeling in invasion and metastasis
Radiotherapy is successfully used to treat a variety of cancers, but recurrence after radiotherapy are associated with increased local invasion, metastatic spreading and poor prognosis. While it is generally assumed that the increased aggressiveness of relapsing tumors is due to the selection of tumor cells resistant to radiation-induced apoptosis, recent results indicate that irradiated stroma promotes tumor progression and metastasis. We are interested in understanding the mechanisms responsible for this effect. Recent work has identified the matricellular protein CYR61 and its receptor integrin alphaVbeta5 as critical mediators of metastasis of tumors growing in irradiated fields.
The current paradigm defines metastasis as a process driving the selection of cells with advantageous traits that allow them to overcome the diverse environmental defenses against the ectopic growth of cells in tissues different from the ones of origin. Many genes involved in promoting metastases have been recently uncovered, including matrix metalloproteinases, chemokines and their receptors, integrins and integrin-dependent signaling events. Many questions remain open in this field. Several important questions remain open at this point. A critical one is the timing of metastasis. Do metastatic cells disseminate early, i.e. at a time when primary tumors are not yet detected, or late, i.e. at a time when primary tumors reach a critical mass, during cancer progression ? How do disseminated cells interact with normal tissue at metastatic sites, in particular in the brain? What is the contribution of bone marrow derived cells to metastasis ? We are pursuing some of these questions using various models of cancer metastasis, mostly of breast cancer.
Several projects conducted in the laboratory are based on clinically relevant questions, with the goal to be able to develop new strategies aimed at improving cancer management and patient quality of live, though improved cancer diagnosis, therapy and monitoring. We are collaborating with several local, national and international cancer centers to design, perform and analyze clinical-laboratory (translational) studies aimed at testing and validating hypothesis based on results generated in the laboratory. Currently ongoing studies include: