腫瘤內皮標誌一亦可稱為內皮唾酸蛋白或CD248，是一個含有C型類凝集素區段的穿膜醣蛋白。它高度表現於周細胞與纖維母細胞。皮膚纖維母細胞在傷口癒合中的增生時期扮演重要的角色。然而，腫瘤內皮標誌一於傷口癒合中的生理功能仍然未知。老鼠背部傷口癒合的過程中，腫瘤內皮標誌一與血小板衍生生長因子接受器會高度表現於肌纖維母細胞。老鼠體內，腫瘤內皮標誌一的基因剔除會減少顆粒組織中纖維母細胞活化與膠原蛋白沉澱且減緩傷口癒合。體外細胞實驗中，腫瘤內皮標誌一的下調控會抑制NIH3T3纖維母細胞的爬行、貼附與增生能力。腫瘤內皮標誌一的下調能夠減緩血小板衍生生長因子所誘發的訊息傳遞、增生及吸引能力。此外，腫瘤內皮標誌一與血小板衍生生長因子接受器共位於纖維母細胞之次細胞胞器。藉由免疫共沉澱法發現腫瘤內皮標誌一與血小板衍生生長因子接受器產生交互作用。腫瘤內皮標誌一與血小板衍生生長因子接受器的交互作用，可藉由增強血小板衍生生長因子誘發的爬行、增生與肌纖維母細胞的膠原蛋白沉澱在傷口癒合扮演重要的角色。另外，腫瘤內皮標誌一專一的表現於類纖維母的細胞中，並參與各種器官的病理性纖維化形成。蟹足腫是一個皮膚上纖維增生的疾病，起因於不正常的傷口癒合。然而，腫瘤內皮標誌一對於影響蟹足腫機制尚未清楚。蟹足腫組織中，腫瘤內皮標誌一的表現上升，並與纖維母細胞活化標誌的表現有著強烈的相關性，這類活化標誌包含了平滑肌動蛋白α、第一型膠原蛋白、纖連蛋白、脯胺醯四羥化酶次單位β、血小板衍生生長因子接受器α。此外，相對於正常纖維母細胞，在蟹足腫纖維母細胞中可以發現腫瘤內皮標誌一表現量的上升。而蟹足腫纖維母細胞有著較強的增生、爬行及侵襲能力。因此，腫瘤內皮標誌一基因下調減少了蟹足腫纖維母細胞的增生、爬行及侵襲。在轉染腫瘤內皮標誌一微小干擾核醣核酸後的皮膚纖維母細胞中，轉化生長因子-β1誘發的訊息傳導與纖維母細胞活化是減緩的。腫瘤內皮標誌一基因下調造成轉化生長因子第二接受器快速降解與caveolin-1蛋白表現的減少。在蟹足腫的組織中，腫瘤內皮標誌一與轉化生長因子第二接受器表現上升，並彼此共位。此外，在皮膚的纖維母細胞中，發現腫瘤內皮標誌一與轉化生長因子第二接受器共位存在於次細胞胞器，並利用免疫共沉澱法證明彼此的交互作用。MORAb-004為對抗腫瘤內皮標誌一的抗體，於異體移植裸鼠膜式中，此抗體能有效縮小蟹足腫病灶大小。這些結果揭開了腫瘤內皮標誌一與轉化生長因子第二接受器彼此有交互作用，藉由調控轉化生長因子誘發的纖維母細胞增生與肌纖維母細胞的轉換，可在纖維母細胞的活化過程中扮演舉足輕重的角色。腫瘤內皮標誌一與轉化生長因子的交互作用，特別對於蟹足腫病理狀態的形成有顯著意義的貢獻。總結來說，適量腫瘤內皮標誌一表現能促進皮膚傷口癒合，然而過量腫瘤內皮標誌一表現會造成蟹足腫疤痕形成。

Tumor endothelial marker 1 (TEM1), also known as endosialin or CD248, is a type I transmembrane glycoprotein containing a C-type lectin-like domain. It is highly expressed in pericytes and fibroblasts. Dermal fibroblasts play a pivotal role in cutaneous wound healing, especially in the proliferative phase. However, the physiological function of TEM1 in wound healing is still undetermined. During the process of wound healing in the back of mice, both TEM1 and platelet-derived growth factor (PDGF) receptor α (PDGFRα) expressions were highly upregulated in myofibroblasts. In vivo, fibroblast activation and collagen deposition in granulation tissues were attenuated in the wound, and wound healing was retarded in TEM1-deleted mice. In vitro, the migration, adhesion, and proliferation of NIH3T3 cells were suppressed following TEM1 knockdown by short hairpin RNA. In PDGF-BB-treated NIH3T3 cells, the downstream signal, mitogenic, and chemoattractive effects were inhibited by TEM1 knockdown. Additionally, TEM1 and PDGFRα were co-localized in sub-cellular organelles in fibroblasts and the association of TEM1 and PDGFRα was demonstrated by co-immunoprecipitation. These findings suggested that TEM1, in combination with PDGFRα, plays a critical role in wound healing by enhancing the mitogenic and chemoattractive effects of PDGF-BB and collagen deposition in myofibroblasts. On the other hand, TEM1 is specifically expressed in fibroblast-like cells and participates in pathological fibrogenesis of multiple organs. Keloid is a type of fibroproliferative skin disease resulting from abnormal wound healing. However, the critical involvement of TEM1 in keloid scars remains unclear. We demonstrated that TEM1 expression was significantly increased in keloid tissues. An increase in TEM1 expression of keloid tissues in comparison to normal tissues was strongly associated with the massively upregulated expression of various activation markers of fibroblasts, including α-smooth muscle actin, type I collagen, fibronectin, prolyl 4-hydroxylase subunit β, and PDGFRα. The elevation of TEM1 expression was observed in keloid fibroblasts compared with normal fibroblasts in vitro. Keloid fibroblasts exhibit higher activities in proliferation, migration and invasion than normal fibroblasts. TEM1 silencing in keloid fibroblasts led to a decrease in activities of the cell proliferation, migration, and invasion. The extent of signal transduction and fibroblast activation induced by transforming growth factor (TGF)-β1 in dermal fibroblasts were alleviated when TEM1 gene expression was suppressed. A rapid degradation of TGF-β receptor II and the increased protein level of caveolin-1 expression were found in TEM1-knockdown dermal fibroblasts. Both TEM1 and TGF-β receptor II expressions were upregulated and co-localized mutually in keloid tissues. Furthermore, TEM1 and TGF-β receptor II were co-localized in sub-cellular organelles in dermal fibroblasts. The interaction of TEM1 and TGF-β receptor II was validated using co-immunoprecipitation. MORAb-004 treatment, which is a humanized monoclonal antibody against TEM1, decreased the lesion size of keloid in xenograft nude mouse model. These results uncovered that TEM1 in cooperation with TGF-β receptor II plays a pivotal role in the activation of fibroblasts by augmenting TGF-β-mediated effects on cell proliferation and transition of dermal fibroblasts to myofibroblasts. The synergistic effect of TEM1 on TGF-β signaling pathway might have a significant contribution to the pathogenesis of keloid. In conclusion, adequate TEM1 expression facilitates cutaneous wound healing, while excessive TEM1 expression leads to keloid scar formation.

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