Control of tumor growth and metastasis by the cytokine TSLP

描述(申请人提供)：癌症相关死亡的主要原因是肿瘤转移，即原发肿瘤侵袭远处的能力。因此，了解肿瘤转移的潜在机制和控制它的因素，是研究肿瘤发生的主要挑战。转移是一个复杂的过程，既涉及肿瘤内在因素(肿瘤细胞的遗传或表观遗传改变)，也涉及肿瘤微环境提供的外在因素。这些外在因素包括肿瘤相关间质细胞和浸润性炎症细胞表达的细胞因子，肿瘤周围细胞外基质的变化，以及肿瘤内血管和/或淋巴管的变化。这些因素结合在一起，创造了一个既能促进肿瘤生长的微环境，又能通过细胞因子的表达和肿瘤特异性免疫抑制(调节性T细胞和髓系来源的抑制细胞)的产生，以及能够分解基质和允许肿瘤逃逸和转移的因子的产生。然而，目前还不清楚这些不同的过程是如何监管的。我们发现细胞因子胸腺间质淋巴生成素(TSLP)在控制转移性乳腺癌中起着至关重要的作用。肿瘤和宿主的TSLP表达调节肿瘤的转移；TSLP的丢失，无论是通过基因破坏还是通过中和，都显著地减少了肿瘤的生长和抑制转移。TSLP还可以诱导髓系抑制细胞的发育，增强其抑制免疫反应的能力。基于这些初步数据，我们建议：1.确定TSLP在肿瘤生长和转移中的作用；2.确定参与肿瘤进展的TSLP调节因子；3.确定TSLP在髓系抑制细胞的发育和功能中的作用。这些研究将为TSLP在转移性乳腺癌中的作用提供重要的见解，并允许对TSLP阻断作为乳腺癌治疗干预措施的临床前评估。

DESCRIPTION (provided by applicant): The leading cause of cancer-associated deaths is tumor metastasis, the ability of the primary tumor to invade distant sites. Thus, an understanding of the underlying mechanism for tumor metastasis, and the factors that control it, is a major challenge studying oncogenesis. Metastasis is a complex involving both tumor-intrinsic factors (genetic or epigenetic alteration to the tumor cells) and extrinsic factors provied by the tumor microenvironment. These extrinsic factors can include cytokines expressed by tumor-associated stromal cells and infiltrating inflammatory cells, changes in the extracellular matrix surrounding the tumor, and alterations in blood and/or lymphatic vessels within the tumor. These factors combine to create a microenvironment that can both promote tumor growth, through the expression of cytokines and the generation of tumor-specific immune suppression (regulatory T cells and myeloid-derived suppressor cells), and the production of factors, such as proteases, capable of breaking down the matrix and allowing the tumor to escape and metastasize. However, it remains unclear how these various processes are regulated. We have found that the cytokine thymic stromal lymphopoietin (TSLP) is critically involved in the control of metastatic breast cancer. TSLP expression by both the tumor and the host regulates tumor metastasis; and loss of TSLP, either genetically through gene disruption or via neutralization, dramatically reduces tumor growth and inhibits metastasis. TSLP can also induce the development of myeloid-derived suppressor cells, and increase their ability to suppress immune responses. Based on this preliminary data, we propose to: 1. Determine the role of TSLP in tumor growth and metastasis; 2. Identify TSLP-regulated factors that are involved in tumor progression; 3. Determine the role of TSLP in the development and function of myeloid-derived suppressor cells. These studies will provide important insights into the role of TSLP in metastatic breast cancer, and allow for preclinical evaluation of TSLP blockade as a therapeutic intervention in breast cancer.