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

在结直肠癌中，转移是导致患者死亡的主要原因。虽然手术切除原发肿瘤和随后的辅助治疗能够治愈癌症，但转移性疾病由于其全身扩散和播散性肿瘤细胞对当前治疗的抵抗力而在很大程度上无法治愈。在实体肿瘤中，众所周知，血管生成从最初的无血管肿瘤结节转变为快速生长的高度血供的肿瘤是关键的一步。为了阻断肿瘤的血管生成和生长，用抗体或酪氨酸激酶抑制剂进行抗血管生成治疗。抗血管生成治疗结合化疗被成功地应用于转移性结直肠癌患者的治疗，这种疾病是我们在海德堡大学医院外科的主要工作重点。然而，并不是所有的患者都对抗血管生成治疗有反应，其他患者也会产生抵抗机制，从而使肿瘤逃脱治疗。因此，有必要更好地了解转移环境中的血管生成。抗血管生成治疗对原发肿瘤的影响已经在基础科学领域得到了深入的研究，即使是顽固的患者，在这个阶段也往往可以通过手术切除肿瘤来治愈。然而，抗血管生成治疗的直接机制以及临床上更相关的肿瘤转移的耐药机制仍不清楚。在本项目中，我们将通过自发性或原位注射的小鼠转移瘤模型来研究血管生成在转移中的机制以及转移瘤微环境在转移血管生成中的作用。我们的兴趣尤其集中在了解巨噬细胞如何支持转移性血管生成以及它们如何参与抗血管生成治疗耐药。通过对转移微环境中内皮细胞和巨噬细胞的表达分析，我们旨在阐明转移中血管生成和抗血管生成治疗耐药的潜在分子机制。所有结果还将在我们医院手术切除的患者的临床肿瘤和转移样本中得到验证。这项建议的总体目标是为转移性肿瘤的靶向抗血管生成治疗奠定基础。

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.