Modulation of the hematopoietic stem cell niche by micrometastases

乳腺癌和前列腺癌等实体瘤的微转移瘤在遇到造血干细胞小生境的微环境时具有早期转移到骨髓的倾向。肿瘤细胞与骨髓小生境组分之间功能性相互作用的分子基础仍然只有部分了解。因此，我们将检验以下假设：I）造血干细胞龛的细胞组分（间充质基质细胞（MSC）和造血干细胞（HSC））的遗传特征和功能是否受到入侵肿瘤细胞的影响; II）破骨细胞是否调节肿瘤细胞向骨髓龛的迁移和归巢。初步数据表明，MSC与肿瘤细胞条件培养基孵育后，趋化因子基质衍生因子-1 α（SDF-1）的mRNA和蛋白水平以时间依赖性和可逆的方式降低。将研究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细胞因子的分泌和破骨细胞在此背景下的潜在作用。该项目的总体目标是描述肿瘤细胞侵袭对骨髓微环境稳态的影响，并确定治疗干预的潜在靶点。

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.