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，转移性疾病在很大程度上是不可治愈的，由于其系统性扩散和扩散的肿瘤细胞对当前therapeutic.In实体瘤，它是公认的血管生成开关从最初的无血管肿瘤结节快速增长的高度血管化的肿瘤是一个关键步骤。为了阻断血管生成和肿瘤的生长，开发了使用抗体或酪氨酸激酶抑制剂的抗血管生成治疗。抗血管生成疗法与化疗一起成功地用于治疗转移性结直肠癌患者，这种疾病是我们在海德堡大学医院外科工作的主要重点。然而，并非所有患者都对抗血管生成疗法有反应，并且其他患者发展出肿瘤逃避疗法的抗性机制。因此，需要更好地了解转移性环境中的血管生成。抗血管生成治疗对原发性肿瘤的影响在基础科学领域已经得到了深入的研究，即使是坚韧患者也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癌症转移中的耐药机制仍然是难以捉摸的。本课题通过建立小鼠自发性或原位注射性转移肿瘤模型，研究肿瘤转移过程中血管生成的机制以及转移肿瘤微环境在肿瘤血管生成中的作用。我们的兴趣特别集中在理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抗性。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抵抗的潜在分子机制。所有结果将在来自我们医院的手术切除患者的临床肿瘤和转移样本中进行额外验证。该提案的总体目标是建立转移性肿瘤靶向抗血管生成治疗的基础。

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.