Modulation of the hematopoietic stem cell niche by micrometastases

实体肿瘤的微转移，如乳腺癌和前列腺癌，如果遇到造血干细胞生态位的微环境，很容易早期转移到骨髓。肿瘤细胞与骨髓龛成分之间的功能相互作用的分子基础仍然只有部分了解。因此，我们将检验假设一)造血干细胞生态位的细胞成分(间充质基质细胞和造血干细胞，HSC)是否受侵袭的肿瘤细胞影响其遗传特征和功能；以及二)破骨细胞是否调节肿瘤细胞向骨髓生态位的迁移和归巢。初步的自身数据表明，间充质干细胞与肿瘤细胞条件培养液孵育后，趋化因子基质衍生因子-1α(SDF-1)的基因和蛋白水平以时间依赖和可逆的方式降低。成骨信号通路的特异性诱导/抑制，以及肿瘤细胞接触后促炎症细胞因子的分泌，以及破骨细胞在这方面的潜在作用将被研究。该项目的总体目标将是描绘肿瘤细胞侵袭对骨髓微环境动态平衡的影响，并确定潜在的治疗干预目标。

Micrometastases of solid tumors like breast and prostate cancer have a predisposition to metastasize early to the bone marrow were they encounter the microenvironment of the hematopoietic stem cell niche. The molecular basis for the functional interaction between tumor cells with the components of the bone marrow niche remains only partially understood. Therefore, we will test the hypothesis I) whether the cellular components of the hematopoietic stem cell niche (mesenchymal stromal cells, MSC, and hematopoietic stem cells, HSC) are influenced in their genetic profile and function by the invading tumor cells; and II) whether osteoclasts modulate the migration and homing of tumor cells into the bone marrow niche. Preliminary own data suggest that mRNA and protein levels of the chemokine stroma-derived factor-1α (SDF-1) are decreased after MSC incubation with tumor cell-conditioned medium in a time-dependent and reversible manner. The specific induction/repression of osteogenic signaling pathways as well as the secretion of proinflammatory cytokines after tumor cell contact and the potential role of osteoclasts in this context will be investigated. The overall goal of the project will be to delineate the impact of tumor cell invasion on the homeostasis of the bone marrow microenvironment and the identification of potential targets for therapeutic interventions.