Secretome Analysis of an Osteogenic Prostate Tumor Identifies Complex Signaling Networks Mediating Cross-talk of Cancer and Stromal Cells Within the Tumor Microenvironment
Secretome Analysis of an Osteogenic Prostate Tumor Identifies Complex Signaling Networks Mediating Cross-talk of Cancer and Stromal Cells Within the Tumor Microenvironment
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DOI：
10.1074/mcp.m114.039909
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发表时间：
2015-03-01
影响因子：
7
通讯作者：
Lin, Sue-Hwa
中科院分区：
文献类型：
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作者：
Lee, Yu-Chen;Gajdosik, Martina Srajer;Lin, Sue-Hwa
人类前列腺癌（PCa）的一个显着特征是成骨细胞（骨形成）骨转移的发生。骨中的转移性生长由PCa细胞分泌的因子支持，所述因子激活肿瘤微环境中的信号传导网络，从而增强肿瘤生长。为了更好地理解这些信号网络并确定骨转移治疗的潜在靶点，我们表征了成骨细胞骨病变产生的患者来源的异种移植物MDA-PCa-118 b（PCa-118 b）的分泌组。PCa-118 b在植入小鼠股骨或皮下时诱导成骨细胞肿瘤。为了研究对这些独特的肿瘤/微环境介导的事件至关重要的信号分子，我们对分离的PCa-118 b肿瘤细胞的条件培养基进行了质谱分析，并鉴定了26种分泌蛋白，如TGF-β 2、GDF 15、FGF 3、FGF 19、CXCL 1、半乳糖凝集素和β 2-微球蛋白，它们代表了新的和先前发表的分泌蛋白。使用人与小鼠特异性引物的RT-PCR显示TGF β 2、GDF 15、FGF 3、FGF 19和CXCL 1从PCa-118 b细胞分泌。TGF β 2、GDF 15、FGF 3和FGF 19在肿瘤细胞和基质细胞（即内皮细胞和成骨细胞）上起自分泌和旁分泌因子的作用。相反，CXCL 1通过内皮细胞和成骨细胞上表达的CXCR 2受体作为旁分泌因子发挥作用。因此，我们的研究揭示了一个复杂的PCa骨转移分泌组，具有旁分泌和自分泌信号传导功能，介导肿瘤微环境中多种细胞类型之间的串扰。
A distinct feature of human prostate cancer (PCa) is the development of osteoblastic (bone-forming) bone metastases. Metastatic growth in the bone is supported by factors secreted by PCa cells that activate signaling networks in the tumor microenvironment that augment tumor growth. To better understand these signaling networks and identify potential targets for therapy of bone metastases, we characterized the secretome of a patient-derived xenograft, MDA-PCa-118b (PCa-118b), generated from osteoblastic bone lesion. PCa-118b induces osteoblastic tumors when implanted either in mouse femurs or subcutaneously. To study signaling molecules critical to these unique tumor/microenvironment-mediated events, we performed mass spectrometry on conditioned media of isolated PCa-118b tumor cells, and identified 26 secretory proteins, such as TGF-beta 2, GDF15, FGF3, FGF19, CXCL1, galectins, and beta 2-microglobulin, which represent both novel and previously published secreted proteins. RT-PCR using human versus mouse-specific primers showed that TGF beta 2, GDF15, FGF3, FGF19, and CXCL1 were secreted from PCa-118b cells. TGF beta 2, GDF15, FGF3, and FGF19 function as both autocrine and paracrine factors on tumor cells and stromal cells, that is, endothelial cells and osteoblasts. In contrast, CXCL1 functions as a paracrine factor through the CXCR2 receptor expressed on endothelial cells and osteoblasts. Thus, our study reveals a complex PCa bone metastasis secretome with paracrine and autocrine signaling functions that mediate cross-talk among multiple cell types within the tumor microenvironment.