Tumor-Derived CCL5 and Breast Cancer Metastasis

描述（由申请人提供）：乳腺癌患者的转移性疾病是最常见的死亡原因。因此，如果要开发新的治疗方法来阻止转移过程和随之而来的死亡，了解导致转移的机制是至关重要的。该项目的目的是确定一种通常由新鲜分离的乳腺癌标本产生的趋化因子是否有助于转移。趋化因子在激活正常T细胞表达和分泌时受到调节（RANTES, CCL5）。肿瘤来源的CCL5与乳腺癌患者的进展和小鼠的免疫抑制有关。该项目将确定肿瘤源性CCL5是否有助于乳腺癌转移。为此，将使用两只小鼠乳腺癌。4T1组成性地产生CCL5，并在皮下生长肿瘤的小鼠中自发转移到脑、肝和肺。为了确定肿瘤源性CCL5是否有助于4T1的转移潜力，我们将使用RNA干扰下调CCL5，并确定CCL5+和CCL5- 4T1的转移能力。除了4T1的研究外，我们还将使用168例小鼠乳腺癌，这些乳腺癌表现出低转移活性，不产生CCL5。168将被CCL5转基因转染，随后将确定CCL5+和CCL5- 168的转移能力。如果CCL5有助于转移，那么抑制肿瘤源性CCL5将与减少脑、肝和肺转移相关，而CCL5的上调将分别与4T1和168肿瘤的转移增强相关。最后，我们将通过将CCL5修饰的肿瘤传递给缺乏T细胞亚群的裸小鼠和Balb/c小鼠，通过调节免疫反应来确定CCL5是否有助于肿瘤细胞的转移能力。总的来说，这个项目将确定CCL5是否有助于乳腺癌转移，以及免疫功能的调节是否对此负责。

DESCRIPTION (provided by applicant): Metastatic disease in patients with breast cancer is the most common cause of death. For this reason understanding the mechanisms that contribute to metastasis is critical if new therapies are to be developed to stop the metastatic process and the death that ensues. The goal of this project is to determine whether a chemokine that is often produced by freshly isolated breast cancer specimens contributes to metastasis. The chemokine is Regulated Upon Activation Normal T cell Expressed and Secreted (RANTES, CCL5). Tumor-derived CCL5 has been associated with progression in patients with breast cancer and immune suppression in mice. This project will determine whether tumor-derived CCL5 contributes to breast cancer metastasis. For this purpose two murine mammary carcinomas will be used. 4T1 constitutively produces CCL5 and spontaneously metastasizes to the brain, liver and lungs in mice bearing subcutaneously growing tumors. To determine whether tumor-derived CCL5 contributes to the metastatic potential of 4T1 we will use RNA interference to down-regulate CCL5 and the metastatic capability of CCL5+ and CCL5- 4T1 will be determined. In addition to the studies with 4T1 we will use the 168 murine mammary carcinoma which exhibits low metastatic activity and does not produce CCL5. 168 will be transfected with the CCL5 transgene and subsequently the metastatic capability of CCL5+ and CCL5- 168 will be determined. If CCL5 contributes to metastasis then inhibition of tumor-derived CCL5 will correlate with decreased brain, liver and lung metastasis, and up-regulation of CCL5 will correlate with enhanced metastasis of the 4T1 and 168 tumors respectively. Finally, we will determine whether CCL5 contributes to the metastatic capability of the tumor cells by modulating the immune response by delivering the CCL5 modified tumors to nude mice and Balb/c mice depleted of T cell subsets. Collectively, this project will determine whether CCL5 contributes to breast cancer metastasis and whether modulation of immune function is responsible.