VEGF signaling in Mammary Tumorigenesis

乳腺肿瘤发生中的 VEGF 信号传导

• 批准号: 9922868
• 负责人: Arthur M Mercurio
• 金额: $ 39.78万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922868
• 关键词: Address; Affect; Biology; Breast cancer metastasis; Cell Differentiation process; Cell physiology; Cells; Complex; Conflict (Psychology); Data; Epithelial; Epithelium; Exhibits; Feedback; Focal Adhesions; Frequencies; Goals; Grant; Growth; Integrin alpha6; Integrin alpha6beta1; Integrin alpha6beta4; Integrin beta4; Integrins; Laminin; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Neoplasm Metastasis; Neuropilins; Paracrine Communication; Population; Property; Regulation; Reporter; Reporting; Repression; Role; Signal Transduction; Testing; Therapeutic Intervention; Transgenic Model; Vascular Endothelial Growth Factors; Work; autocrine; base; cancer stem cell; experimental study; in vivo; malignant breast neoplasm; mechanotransduction; neoplastic cell; novel; parathyroid hormone-related protein; protein expression; receptor; self-renewal; stem cell differentiation; stem cell population; stem cells; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor initiation

This proposal will examine the unanticipated hypothesis that the α6β4 integrin (referred to as `β4') contributes to the initiation and metastasis of breast tumors by a non-cell autonomous mechanism. This hypothesis derives from the observations that the expression of β4 is low or absent in breast cancer stem cells (CSCs) but that it contributes to the formation and metastasis of breast cancers. A major goal of this proposal is to reconcile these discrepant observations and understand how β4 contributes to tumor formation and metastasis. Interestingly, triple-negative breast cancers (TNBCs) contain a distinct sub-population of cells characterized by high expression of the β4 integrin (β4high) that is distinct from CSCs (β4-/low/CD24low/CD44high), exhibits basal epithelial differentiation and lacks stem cell properties. These observations indicate that repression of β4 is necessary for CSC function. In fact, we observed unexpectedly that β4 expression in CSCs promotes their differentiation and inhibits their self-renewal. The first specific aim will investigate the mechanism that underlies this phenomenon and it will focus on the exciting possibility that it involves the ability of β4 to modulate focal adhesions and cytoskeletal tension resulting in diminished stem cell properties. This aim will also test the possibility that alterations in cytoskeletal tension have a causal role in promoting the differentiation of CSCs. The second specific aim will evaluate the hypothesis that the β4high sub-population exerts non-cell autonomous regulation of CSCs. In other terms, a key function of the β4high subpopulation is to expand the CSC population. More specifically, it is proposed that this distinct sub-population engages in paracrine signaling with CSCs mediated by parathyroid hormone-related protein (PTHrP) and that this signaling contributes to the expansion of CSCs. This hypothesis is based on the observations that β4 regulates PTHrP expression and that the β4high sub-population and CSCs are in proximity in breast tumors. Also, our preliminary data indicate that the β4high sub-population helps to maintain self-renewal and survival. These observations provide an explanation for how the β4 integrin contributes to tumor initiation and metastasis without being expressed in CSCs. The final specific aim will study the relationship between CSCs and β4high cells in vivo and evaluate their relative contribution to tumor initiation and metastasis. The first set of experiments will examine whether both CSCs and β4high cells are required for efficient tumor formation and metastasis using a transgenic model of TNBC. The second sub-aim probe more deeply into the relationship between CSCs and β4high cells by evaluating the extent to which CSCs differentiate in vivo and assessing their association with β4high cells in niches. These goals will be facilitated by the use of reporter constructs to tag these distinct populations. This approach will allow us to address several key issues including the frequency that CSCs (GFP+) differentiate in vivo, the association of β4high and CSCs in `niches' and the relative frequency of CSCs and β4high cells in metastases.

该提案将审查意外的假设，即α6β4整合素（称为“β4”）有助于 通过非细胞自主机制对乳腺肿瘤的启动和转移。这个假设 源自乳腺癌干细胞（CSC）中β4表达低或不存在的观察结果 它有助于乳腺癌的形成和转移。该提议的主要目标是 调和这些差异观察，并了解β4如何促进肿瘤形成和转移。 有趣的是，三阴性乳腺癌（TNBC）包含一个明显的细胞亚群，以 与CSC（β4-/Low/low/cd24low/cd44high）不同的β4整联蛋白（β4High）的高表达表现为碱性 上皮分化，缺乏干细胞特性。这些观察结果表明β4的表达为 CSC功能所需的。实际上，我们意外地观察到CSC中的β4表达促进了它们 分化并抑制他们的自我更新。第一个具体目的将调查以下机制 这是这种现象的基础，它将集中在涉及β4能力的令人兴奋的可能性上 调节局灶性粘合剂和细胞骨架张力，导致干细胞特性降低。这个目标 还测试细胞骨架张力改变在促进分化中具有因果作用的可能性 CSC。 第二个特定目的将评估β4High子人群执行非电池自主的假设 CSC的调节。换句话说，β4高亚群的关键功能是扩大CSC群体。 更具体地说，建议这种独特的子群与CSC进行旁分泌信号传导 由甲状旁腺激素相关蛋白（PTHRP）介导的，该信号有助于扩张 CSC。该假设是基于β4调节PTHRP表达和β4高的观察结果 乳腺肿瘤中的亚群和CSC处于接近。另外，我们的初步数据表明β4高 子人群有助于维持自我更新和生存。这些观察为 β4整联蛋白如何有助于肿瘤的启动和转移，而不会在CSC中表达。 最终的具体目的将研究体内CSC和β4高细胞之间的关系，并评估它们 对肿瘤倡议和转移的相对贡献。第一组实验将检查是否 使用CSC和β4高细胞进行有效的肿瘤形成和转移需要使用的转基因模型 TNBC。通过 评估CSC在多大程度上区分体内并评估其与β4高细胞中的关联 利基。这些目标将通过使用记者结构来标记这些不同的人群来制定。这 方法将使我们能够解决几个关键问题，包括CSC（GFP+）区分的频率 体内，“壁ches”中β4高和CSC的关联以及CSC和β4高细胞的相对频率 转移。