Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
The Wistar Institute, Philadelphia, Pennsylvania.
Cancer Discov. 2019 Jan;9(1):82-95. doi: 10.1158/2159-8290.CD-18-0168. Epub 2018 Oct 2.
Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inability to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. , reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics. SIGNIFICANCE: Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment...
老年黑色素瘤患者的前哨淋巴结 (LN) 转移率较低,但生存状况却较差。在 1000 多名患者中,有超过 1000 名患者的前哨淋巴结活检过程中,患者年龄与无法保留锝放射性示踪剂之间存在相关性,而锝计数高则与更好的生存相关。我们假设,由于细胞外基质 (ECM) 降解导致淋巴管完整性丧失可能发挥作用。我们已经发现 HAPLN1 在真皮中与年龄相关的 ECM 降解有关。在这里,我们询问 HAPLN1 是否可以在前哨淋巴结的 ECM 中发生改变。淋巴 HAPLN1 的表达与患者的长期生存预后相关。向老年成纤维细胞 ECM 添加重组 HAPLN1 通过调节 VE-钙粘蛋白连接来降低内皮通透性,而在年轻成纤维细胞中敲低 HAPLN1 后内皮通透性增加。在年老的小鼠中重建 HAPLN1 增加了 LN 转移的数量,但减少了内脏转移。这些数据表明,ECM 中的年龄相关变化可能导致淋巴管功能受损。意义:我们的研究表明,衰老过程中基质的变化可能会影响肿瘤细胞通过淋巴管的方式。衰老可能决定了肿瘤细胞转移的途径,了解这些变化可能有助于揭示衰老肿瘤微环境中的靶向部位。
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