Furuhashi Masao, Sjöblom Tobias, Abramsson Alexandra, Ellingsen Jens, Micke Patrick, Li Hong, Bergsten-Folestad Erika, Eriksson Ulf, Heuchel Rainer, Betsholtz Christer, Heldin Carl-Henrik, Ostman Arne
Ludwig Institute for Cancer Research, Uppsala Branch, Uppsala, Sweden.
Cancer Res. 2004 Apr 15;64(8):2725-33. doi: 10.1158/0008-5472.can-03-1489.
Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. In the present study, the B16 mouse melanoma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or PDGF-DD by tumor cells was associated with an increased tumor growth rate. Characterization of tumors revealed an increase in pericyte abundance in tumors derived from B16 cells producing PDGF-BB or PDGF-DD. The increased tumor growth rate associated with PDGF-DD production was not seen in mice expressing an attenuated PDGF beta-receptor and was thus dependent on host PDGF beta-receptor signaling. The increased pericyte abundance was not associated with an increased tumor vessel density. However, tumor cell apoptosis, but not proliferation, was reduced in tumors displaying PDGF-induced increased pericyte coverage. Our findings thus demonstrate that paracrine PDGF production stimulates pericyte recruitment to tumor vessels and suggest that pericyte abundance influences tumor cell apoptosis and tumor growth.
血小板衍生生长因子（PDGF）受体信号传导参与实体瘤的不同过程，包括肿瘤细胞生长的自分泌刺激、肿瘤基质成纤维细胞的募集以及肿瘤血管生成的刺激。在本研究中，使用B16小鼠黑色素瘤肿瘤模型来研究旁分泌PDGF刺激宿主来源细胞的功能后果。肿瘤细胞产生PDGF-BB或PDGF-DD与肿瘤生长速率增加有关。对肿瘤的表征显示，在源自产生PDGF-BB或PDGF-DD的B16细胞的肿瘤中，周细胞丰度增加。在表达减弱的PDGFβ受体的小鼠中未观察到与PDGF-DD产生相关的肿瘤生长速率增加，因此其依赖于宿主PDGFβ受体信号传导。周细胞丰度增加与肿瘤血管密度增加无关。然而，在显示PDGF诱导的周细胞覆盖增加的肿瘤中，肿瘤细胞凋亡减少，而不是增殖减少。因此，我们的研究结果表明，旁分泌PDGF的产生刺激周细胞募集到肿瘤血管，并表明周细胞丰度影响肿瘤细胞凋亡和肿瘤生长。
