Hypoxia Response in the Stroma During Tumorigenesis

描述(由申请人提供)：本更新描述了以乳腺为模型组织的实验，以研究缺氧反应转录因子HIF-1在生长、分化和转化中的作用。很明显，HIF在人类乳腺癌的发展中是一个负面因素，它在原发肿瘤中的存在表明这种疾病的预后很差。因此，更好地了解它在进展中的作用具有明显的相关性，不仅与对缺氧反应和恶性肿瘤的基本了解有关，而且对乳腺癌女性的临床应用也有明显的相关性。在这项关于HIF和恶性肿瘤的工作中，我们建议使用在最后一期资助中获得的见解和产生的试剂来研究恶性组织的缺氧反应，重点是它们在转移过程中与其他组织的相互作用。转移是癌症的中心问题，在某些方面，治疗和预防转移疾病是癌症治疗的最重要目标。我们发现，当恶性乳腺组织缺乏HIF-1a时，转移显著减少。这一发现表明，这一转录途径在允许恶性细胞经历转移过程中起着关键作用，并暗示转移事件和缺氧反应之间存在交叉。在另一项意想不到的发现中，我们发现内皮细胞中HIF-1a的缺失会导致体内转移的大幅减少。这两项调查结果是我们为这笔赠款的第三期支助提出的三个具体目标的基础。该提案的具体目的是：具体目标1：确定HIF反应在恶性上皮细胞黏附和跨细胞反应中的作用。特异性目的2：探讨HIF-1a在乳腺癌转移中的作用。特异靶向3：确定上皮血管内皮生长因子在乳腺肿瘤发生和转移中的作用。公共卫生相关性：转移是癌症的中心问题；在某些方面，治疗和预防转移疾病是癌症治疗的最重要目标。我们发现，当恶性组织缺乏HIF-1a时，转移显著减少。随着我们发现HIF和低氧反应在肿瘤发生中的重要作用，我们认为下一个前沿在于了解肿瘤发生发展的终末阶段：转移事件。

DESCRIPTION (provided by applicant): This renewal describes experiments using the mammary gland as a model tissue for study of the role of the hypoxic response transcription factor, HIF-1, in growth, differentiation and transformation. It is clear that HIF is a negative factor in human breast cancer progression and that its presence in primary tumors indicates a poor prognosis for this disease. Thus, a better understanding of its role in progression has clear relevance, not just to basic understanding of hypoxic response and malignancy, but to clinical application in women with breast cancer. In this work on HIF and malignancy, we propose to use the insights gained and the reagents generated in the last period of funding to study hypoxic responses of malignant tissue, with an emphasis on their interactions with other tissues during metastatic progression. Metastasis is a central problem in cancer; in some respects, treatment and prevention of metastatic disease is the most important goal in cancer therapy. We have found that metastases are significantly reduced when malignant mammary tissue lacks HIF-1a. This finding demonstrates that this transcriptional pathway plays a key role in allowing the malignant cell to undergo the process of metastasis, and implies an intersection between the events of metastasis and those of hypoxic response. In another unexpected finding, we have shown that loss of HIF-1a in the endothelial cell results in a large reduction of metastasis in vivo. These two findings represent the foundations of the three specific aims that we are proposing for the third period of support for this grant. The specific aims of this proposal are: Specific aim 1: Determine the role of HIF response during malignant epithelial adhesion and transcytosis. Specific Aim 2: Determine the role of HIF-1a in the metastasis of mammary carcinomas. Specific aim 3: Determine the role of epithelial VEGF expression during mammary tumorigenesis and metastasis. PUBLIC HEALTH RELEVANCE: Metastasis is a central problem in cancer; in some respects, treatment and prevention of metastatic disease is the most important goal in cancer therapy. We have found that metastases are significantly reduced when malignant tissue lacks HIF-1a. As we have found important roles for HIF and hypoxic response in tumorigenesis, here we believe that the next frontier lies in understanding the terminal stage of tumorigenic progression: the metastatic event.