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

摘要 为了生存，生长和转移，肿瘤需要有利的宿主环境的支持。当地 靠近发展中肿瘤的正常细胞的变化可以创造有利的肿瘤微环境 (TME)是肿瘤生长所必需的间充质细胞群，包括癌症相关成纤维细胞 （CAFs），分泌促肿瘤发生和免疫抑制因子，并产生细胞外基质，以产生细胞外基质。 更坚硬的肿瘤土壤已经确定了几个具有特定功能的CAF子集，然而， 不同的CAF亚群来源于在肿瘤进展期间获得功能特异性的相同祖细胞 或来自不同的祖细胞，致力于产生特定的CAF群体，正在研究中。 我们最近意外地观察到，表达骨成骨细胞标志物Osterix（Osx）的细胞是 存在于骨外肿瘤的TME中并支持肿瘤生长。在成年动物中，Osx表达为 定向成骨细胞（OB）并驱动其分化。令人惊讶的是，我们在基质细胞中检测到Osx， 从各种乳腺癌肿瘤中分离，表达CAF和OB标记，并存在于肿瘤相关基质中 乳腺癌的患者。Osx+细胞与肿瘤细胞的共注射增强肿瘤生长。 重要的是，Osx表达与乳腺癌的不良预后相关。基于这些出乎意料的 研究结果，我们假设骨源性骨系Osx+细胞代表了肿瘤浸润的一个新的亚群， 间质细胞群有助于肿瘤进展和CAF多样性。目标1将确定功能 TME和转移前部位中Osx+细胞的相关性;目标2将确定TME和转移前部位中Osx+细胞的来源。 TME和转移前部位。这一信息将拓宽TME内细胞异质性的概念 并为靶向间质以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.