Understanding Breast Cancer Metastasis to Lymph Node

了解乳腺癌淋巴结转移

• 批准号: 9096548
• 负责人: Sulma Ibrahim Mohammed
• 金额: $ 20.23万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096548
• 关键词: Address; Animal Model; Benign; Blood; Blood Circulation; Breast Cancer Cell; Breast Cancer Model; Breast cancer metastasis; Carcinoma; Cause of Death; Cells; Communities; Distant; Drainage procedure; Excision; Female; Gene Expression; Goals; Growth; Homing; Human; IRF3 gene; Immune; Immunocompetent; Indiana; Infection; Interferons; Invaded; Laboratories; Lead; Left; Ligands; Liquid substance; Lymph; Lymphatic; Lymphatic Metastasis; Lymphatic System; Lymphocyte; Lymphokines; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mediator of activation protein; Medical; Metastatic Neoplasm to Lymph Nodes; Metastatic breast cancer; Modeling; Molecular; NF-kappa B; Neoplasm Circulating Cells; Neoplasm Metastasis; Newly Diagnosed; Nitrogen; Pathway interactions; Population; Positive Lymph Node; Prevention therapy; Primary Neoplasm; Proteins; Rattus; Receptor Cell; Receptor Signaling; Rodent; Rodent Model; Role; Sampling; Sentinel Lymph Node; Signal Pathway; Signal Transduction; Site; Slide; Staging; Stream; Surgeon; System; TLR3 gene; Technology; Testing; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Universities; Woman; Work; cancer cell; chemokine; cytokine; in vivo; innovation; laser capture microdissection; lymph nodes; lymphatic circulation; malignant breast neoplasm; medical schools; nano-string; neoplastic cell; novel; outcome forecast; pathogen; public health relevance; success; three dimensional cell culture; tumor

 DESCRIPTION (provided by applicant): Cancer metastasis, not the primary tumor, is the main cause of death from breast cancer. To metastasize, a cancer cell must leave the primary tumor, survive in blood or lymphatic circulation, invade and colonize distant tissues and establish metastatic foci. Most carcinomas are thought to disseminate via the blood stream and the lymphatic system in parallel. Lymph node metastases are thought to arise from tumor cells that have entered the natural lymphatic drainage of the breast tissue to colonize the downstream sentinel nodes. Beyond this general level of understanding about lymphatic metastasis, there are fundamental biologic questions about lymphatic dissemination that remain unanswered such as: How do tumor cells enter the lymphatic drainage? What is the efficacy of lymphatic metastasis in vivo? Do metastatic and non-metastatic tumors both shed cells into the lymphatic drainage? Are the tumor cells that enter the lymphatic drainage a specialized subset of the parental tumor population? What specialized molecular mechanisms do these cells use to enter the lymph, thrive in the lymph fluid, and colonize the lymph node? To answer these questions, first, our laboratory has developed an innovative microsurgical technology to collect lymph, and the lymph circulating tumor cells (LCTC) contained therein, in an immunocompetent breast cancer animal model. Subsequently, in a collaborative effort with medical surgeons in our community, and those in Indiana University School of Medicine, we successfully applied this same technology to collect, for the first time, LCTC entering the lymph drainage in women with metastatic breast cancer. Second, we propose that the Toll-Like Receptor (TLR) signaling pathways is a major molecular determinant of tumor cell entry into the lymphatic drainage. TLR signaling is known to regulate pathogen sensing and homing of immune cells. This pathway also regulates cytokine and lymphokine release that are part of lymph node activation during the early stages of infection. In the present proposal we will evaluate expression levels of TLRs and key proteins associated with TLR cell signaling pathways for the first time in breast cancer cells (LCTC) entering the lymphatic drainage in the rat model of breast cancer as well as in women with breast cancer. We will use these unique cells (LCTC) to evaluate the functional role of activating or suppressing the TLR pathway on the extent of lymph node metastasis in the rodent model. In women with breast cancer we will correlate expression levels of TLRs and proteins associated with TLR signaling pathways in LCTC with the extent of metastasis in the sentinel node. Understanding the factors that contribute to the first step of lymph node metastasis can lead to a new class of therapies that suppress dissemination, essentially turning a malignant tumor into a benign tumor. Direct access to the tumor cells entering the lymph circulation provides a completely novel paradigm for prognosis and individualized therapy.

 描述(申请人提供)：乳腺癌的主要死因是癌症转移，而不是原发肿瘤。为了转移，癌细胞必须离开原发肿瘤，在血液或淋巴循环中存活，侵袭和定植远处组织，并建立转移灶。大多数癌症被认为是通过血流和淋巴系统平行传播的。淋巴转移被认为是由于肿瘤细胞进入乳腺组织的自然淋巴引流而定植于下游哨兵结节。除了对淋巴转移的这种一般水平的了解之外，还有一些关于淋巴转移的基本生物学问题仍然没有得到回答，例如：肿瘤细胞如何进入淋巴引流？体内淋巴转移的疗效是什么？转移性和非转移性肿瘤是否都将细胞排入淋巴引流？进入淋巴引流的肿瘤细胞是亲代肿瘤群体中的一个特殊亚群吗？这些细胞使用什么特殊的分子机制进入淋巴，在淋巴液中茁壮成长，并在淋巴结内定居？为了回答这些问题，首先，我们的实验室开发了一种创新的显微外科技术，在免疫活性乳腺癌动物模型中收集淋巴及其所含的淋巴循环肿瘤细胞(LCTC)。随后，在与我们社区的外科医生和印第安纳大学医学院的医生的合作下，我们成功地应用了同样的技术，首次收集到转移性乳腺癌女性淋巴引流中的LCTC。第二，我们认为Toll样受体(TLR)信号通路是肿瘤细胞进入淋巴引流的主要分子决定因素。已知TLR信号调节病原体的感知和免疫细胞的归巢。这一途径还调节细胞因子和淋巴因子的释放，而细胞因子和淋巴因子是感染早期淋巴结激活的一部分。在目前的方案中，我们将首次评估TLR和与TLR细胞信号通路相关的关键蛋白在乳腺癌大鼠模型和女性乳腺癌模型中进入淋巴引流的乳腺癌细胞(LCTC)中的表达水平。我们将使用这些独特的细胞(LCTC)来评估激活或抑制TLR通路在啮齿动物模型中对淋巴结转移程度的功能作用。在女性乳腺癌患者中，我们将TLRs和与TLR信号通路相关的蛋白在LCTC中的表达水平与前哨淋巴结的转移程度相关联。了解导致淋巴结转移的第一步的因素可以导致一类新的治疗方法来抑制转移，从本质上将恶性肿瘤转变为良性肿瘤。直接进入淋巴循环的肿瘤细胞为预后和个体化治疗提供了一个全新的范例。