Role of Osterix+ Osteolineage Cells in Primary and Metastatic Breast Cancer

摘要 为了生存、生长和转移，肿瘤需要良好的宿主环境的支持。本地 接近正在发展的肿瘤的正常细胞的变化可以创造有利的肿瘤微环境 (TME)这是肿瘤生长所必需的。间充质细胞群，包括癌症相关的成纤维细胞 (CAF)，分泌促肿瘤和免疫抑制因子，并产生细胞外基质，以创造 更硬的、有利于肿瘤生长的土壤。然而，已经确定了几个具有特定功能的CAF亚集，无论是 不同的CAF亚群来自同一祖细胞，在肿瘤进展过程中获得功能特异性 或来自不同的祖先致力于产生特定的咖啡馆人口，正在调查中。 我们最近进行了一项意想不到的观察，即表达骨线化标志物Osterix(OSX)的细胞 存在于骨外肿瘤的TME中，支持肿瘤生长。在成年动物中，OSX表达为 致力于成骨细胞(OB)并促进其分化。令人惊讶的是，我们在基质细胞中检测到了OSX， 从多种乳腺癌肿瘤中分离出来，表达CAF和OB标记，并在肿瘤相关间质中表达 乳腺癌患者的比例。OSX+细胞与肿瘤细胞共注射可促进肿瘤生长。 重要的是，OSX的表达与乳腺癌预后不良有关。基于这些相当出乎意料的 结果，我们假设骨源性OSX+细胞代表一种新的肿瘤浸润性亚群 间质种群有助于肿瘤进展和CAF多样性。目标1将确定功能 OSX+细胞在TME和转移前部位的相关性；AIM 2将确定OSX+细胞在TME中的来源 TME和转移前部位。这些信息将拓宽TME内细胞异质性的概念 为靶向间质、抑制肿瘤生长提供了新的平台。

ABSTRACT In order to survive, grow and metastasize, tumors need the support of a favorable host environment. Local changes in normal cells in close proximity to a developing tumor can create a favorable tumor micro-environment (TME) that is necessary for tumor growth. Mesenchymal populations, including cancer-associated fibroblasts (CAFs), secrete pro- tumorigenic and immune suppressive factors, and produce extracellular matrix to create a stiffer, tumor-conducive soil. Several CAF subsets with specific functions have been identified, however, whether distinct CAF subsets derive from the same progenitor that acquire functional specificity during tumor progression or from different progenitors committed to give rise to a specific CAF population, is under investigation. We recently made the unexpected observation that cells expressing bone osteolineage marker Osterix (Osx) are present in the TME of tumors outside the bone and support tumor growth. In adult animals, Osx is expressed by committed osteoblasts (OB) and drives their differentiation. Surprisingly, we detected Osx in stromal cells, isolated from various breast cancer tumors, expressing CAF and OB makers, and in the tumor-associated stroma of patients with breast carcinomas. Co-injection of Osx+ cells with tumor cells enhance tumor growth. Importantly, Osx expression correlates with poor prognosis in breast cancer. Based on these rather unexpected findings, we hypothesize that bone-derived osteolineage Osx+ cells represent a novel subset of tumor infiltrating stromal populations contributing to tumor progression and CAF diversity. Aim 1 will determine the functional relevance of Osx+ cells in the TME and pre-metastatic sites; Aim 2 will determine the origin of Osx+ cells in the TME and pre-metastatic sites. This information will broaden the concept of cellular heterogeneity within the TME and offer a new platform for targeting the stroma with the purpose of inhibiting tumor growth.