Sundberg C, Branting M, Gerdin B, Rubin K
Department of Medical and Physiological Chemistry, University Hospital, Uppsala, Sweden.
Am J Pathol. 1997 Aug;151(2):479-92.
Mechanisms underlying stimulation of platelet-derived growth factor (PDGF) beta-receptors expressed on connective tissue cells in human colorectal adenocarcinoma were investigated in this study. PDGF-AB/BB, but not PDGF receptors, was expressed by tumor cells in situ, as well as in tumor cell isolates of low passage from human colorectal adenocarcinoma. In an experimental co-culture system, conditioned medium from tumor cells only marginally activated PDGF beta-receptors expressed on fibroblasts. In contrast, co-culturing of the two cell types led to a marked PDGF beta-receptor activation. Functional PDGF-AB/BB was found to be associated with heparinase-I-sensitive components on the tumor cell surface. PDGF-AB/BB, isolated from heparinase-I-sensitive cell surface components, induced a marked activation of PDGF beta-receptors. Furthermore, co-culturing tumor cells together with fibroblasts led to a sustained activation of PDGF beta-receptors expressed on fibroblasts. Double immunofluorescence staining of tissue sections from human colorectal adenocarcinoma, combined with computer-aided image analysis, revealed that nonproliferating tumor cells were the predominant cellular source of PDGF-AB/BB in the tumor stroma. In addition, PDGF-AB/BB-expressing tumor cells were found juxtapositioned to microvascular cells expressing activated PDGF beta-receptors. Confocal microscopy revealed a cytoplasmic and cell-membrane-associated expression of PDGF-AB/BB in tumor cells situated in the stroma. In contrast, epithelial cells situated in normal or tumorous acinar structures revealed only a cell-membrane-associated PDGF-AB/BB expression. The is vitro and in situ results demonstrate that tumor cells not only facilitate but also have the ability to modulate connective tissue cell responsiveness to PDGF-AB/BB in a paracrine fashion, through direct cell-cell interactions in human colorectal adenocarcinoma.
本研究对人类结肠直肠癌中结缔组织细胞上表达的血小板衍生生长因子（PDGF）β受体的刺激机制进行了研究。原位肿瘤细胞以及来自人类结肠直肠癌的低传代肿瘤细胞分离株均表达PDGF-AB/BB，但不表达PDGF受体。在一个实验性共培养系统中，肿瘤细胞的条件培养基仅轻微激活成纤维细胞上表达的PDGFβ受体。相比之下，两种细胞类型的共培养导致了显著的PDGFβ受体激活。发现功能性PDGF-AB/BB与肿瘤细胞表面对肝素酶-I敏感的成分相关。从对肝素酶-I敏感的细胞表面成分中分离出的PDGF-AB/BB诱导了PDGFβ受体的显著激活。此外，肿瘤细胞与成纤维细胞的共培养导致成纤维细胞上表达的PDGFβ受体持续激活。对人类结肠直肠癌组织切片进行双重免疫荧光染色，并结合计算机辅助图像分析，结果显示非增殖性肿瘤细胞是肿瘤基质中PDGF-AB/BB的主要细胞来源。此外，发现表达PDGF-AB/BB的肿瘤细胞与表达激活的PDGFβ受体的微血管细胞并列。共聚焦显微镜检查显示，位于基质中的肿瘤细胞中PDGF-AB/BB呈细胞质和细胞膜相关表达。相比之下，位于正常或肿瘤腺泡结构中的上皮细胞仅显示细胞膜相关的PDGF-AB/BB表达。体外和原位结果表明，在人类结肠直肠癌中，肿瘤细胞不仅通过直接的细胞间相互作用促进，而且有能力以旁分泌方式调节结缔组织细胞对PDGF-AB/BB的反应性。
Zotero 插件
