Angiogenesis and anti-angiogenic therapy in colorectal cancer metastases - Role of macrophages in the metastatic microenvironment

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In colorectal cancer, metastases are the leading cause of death in patients. Whereas surgical resection of the primary tumor with subsequent adjuvant therapy is able to cure cancer, metastatic disease is largely not curable due to its systemic spread and resistance of disseminated tumor cells to current therapies.In solid tumors, it is well established that the angiogenic switch from an initial avascular tumor nodule to a rapidly growing highly vascularized tumor is a critical step. To block the vascularization and the growth of tumors, the anti-angiogenic therapy with antibodies or tyrosine kinase inhibitors was developed. Anti-angiogenic therapy together with chemotherapy is successfully used in the treatment of patients with metastatic colorectal cancer and this disease is a main focus of our work at the surgical department of the University Hospital in Heidelberg. However not all patients respond to anti-angiogenic therapy and others develop resistance mechanisms with which the tumors escape the therapy. Therefore the need exists to understand better angiogenesis within the metastatic setting. The effect of anti-angiogenic therapy on the primary tumor has been thoroughly studied in the basic science field, even tough patients are often curable at this stage of the disease by surgical tumor resection. However, the direct mechanisms of anti-angiogenic therapy as well as resistance mechanisms within the clinically more relevant cancer metastasis are still elusive. In this project we will study the mechanisms of angiogenesis in the metastasis and the role of the metastatic tumor microenvironment in metastatic angiogenesis by using either spontaneous or orthotopic injectable metastatic mouse tumor models. Our interest is especially focused on the understanding how macrophages are supporting metastatic angiogenensis and how they are involved in anti-angiogenic therapy resistance. By using expression analysis in endothelial cells and macrophages of the metastatic microenvironment, we aim to elucidate the underlying molecular mechanism of angiogeneis and anti-angiogenic therapy resistance within the metastasis. All results will be additionally validated in clinical tumor and metastasis samples from surgically resected patients from our hospital. The overall goal of this proposal is to establish the basis of a targeted anti-angiogenic therapy in metastatic tumors.