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至关重要。这个项目的目标是确定是否是一种趋化因子，往往是由新鲜分离的乳腺癌标本有助于转移。趋化因子在正常T细胞表达和分泌的活化后被调节（RANTES，CCL 5）。肿瘤来源的CCL 5与乳腺癌患者的进展和小鼠的免疫抑制有关。该项目将确定肿瘤来源的CCL 5是否有助于乳腺癌转移。为此，将使用两种鼠乳腺癌。4 T1组成型产生CCL 5，并在皮下生长肿瘤的小鼠中自发转移到脑、肝和肺。为了确定肿瘤来源的CCL 5是否有助于4 T1的转移潜力，我们将使用RNA干扰来下调CCL 5，并确定CCL 5+和CCL 5 - 4 T1的转移能力。除了使用4 T1的研究之外，我们还将使用168只小鼠乳腺癌，其表现出低转移活性并且不产生CCL 5。将用CCL 5转基因转染CCL 5 - 168，随后测定CCL 5+和CCL 5 - 168的转移能力。如果CCL 5有助于转移，则肿瘤来源的CCL 5的抑制将与脑、肝和肺转移的减少相关，并且CCL 5的上调将分别与4 T1和168肿瘤的转移增强相关。最后，我们将确定CCL 5是否有助于肿瘤细胞的转移能力，通过将CCL 5修饰的肿瘤递送到裸鼠和T细胞亚群耗尽的Balb/c小鼠来调节免疫应答。总的来说，该项目将确定CCL 5是否有助于乳腺癌转移以及免疫功能的调节是否负责。

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.