Origins of the Tumor Microenvironment: Quantitative Assessment of Adipose-Derived and Bone Marrow–Derived Stroma

To meet the requirements for rapid tumor growth, a complex array of non-neoplastic cells are recruited to the tumor microenvironment. These cells facilitate tumor development by providing matrices, cytokines, growth factors, as well as vascular networks for nutrient and waste exchange, however their precise origins remain unclear. Through multicolored tissue transplant procedures; we have quantitatively determined the contribution of bone marrow-derived and adipose-derived cells to stromal populations within syngeneic ovarian and breast murine tumors. Our results indicate that subpopulations of tumor-associated fibroblasts (TAFs) are recruited from two distinct sources. The majority of fibroblast specific protein (FSP) positive and fibroblast activation protein (FAP) positive TAFs originate from mesenchymal stem/stromal cells (MSC) located in bone marrow sources, whereas most vascular and fibrovascular stroma (pericytes, α-SMA+ myofibroblasts, and endothelial cells) originates from neighboring adipose tissue. These results highlight the capacity for tumors to utilize multiple sources of structural cells in a systematic and discriminative manner.

为满足肿瘤快速生长的需求，机体将募集大量非肿瘤细胞至肿瘤微环境（tumor microenvironment, TME）中。这些细胞通过提供细胞外基质、细胞因子、生长因子以及参与营养与废物交换的血管网络来促进肿瘤发展，但其确切来源仍未明确。本研究通过多色组织移植技术，定量分析了骨髓来源细胞与脂肪来源细胞对同基因卵巢及乳腺小鼠肿瘤间质细胞群的贡献度。研究结果显示，肿瘤相关成纤维细胞（tumor-associated fibroblasts, TAFs）的亚群可通过两种不同的来源被招募至肿瘤部位。大部分成纤维细胞特异性蛋白（fibroblast specific protein, FSP）阳性与成纤维细胞活化蛋白（fibroblast activation protein, FAP）阳性的TAFs源自骨髓来源的间充质干细胞/基质细胞（mesenchymal stem/stromal cells, MSC）；而大多数血管及纤维血管间质（包括周细胞、α平滑肌肌动蛋白（α-smooth muscle actin, α-SMA）阳性肌成纤维细胞与内皮细胞）则源自邻近的脂肪组织。上述研究结果凸显了肿瘤能够以系统性且具有选择性的方式利用多种结构细胞来源的能力。