Platelets participate in not only thrombosis and hemostasis but also other pathophysiological processes, including tumor metastasis and inflammation. However, the putative role of platelets in the development of solid organs has not yet been described. Here, we report that platelets regulate lung development through the interaction between the platelet-activation receptor, C-type lectin-like receptor-2 (Clec-2; encoded by ), and its ligand, podoplanin, a membrane protein. Clec-2 deletion in mouse platelets led to lung malformation, which caused respiratory failure and neonatal lethality. In these embryos, α-smooth muscle actin-positive alveolar duct myofibroblasts (adMYFs) were almost absent in the primary alveolar septa, which resulted in loss of alveolar elastic fibers and lung malformation. Our data suggest that the lack of adMYFs is caused by abnormal differentiation of lung mesothelial cells (luMCs), the major progenitor of adMYFs. In the developing lung, podoplanin expression is detected in alveolar epithelial cells (AECs), luMCs, and lymphatic endothelial cells (LECs). LEC-specific podoplanin knockout mice showed neonatal lethality and-like lung developmental abnormalities. Notably, these -like lung abnormalities were also observed after thrombocytopenia or transforming growth factor-β depletion in fetuses. We propose that the interaction between Clec-2 on platelets and podoplanin on LECs stimulates adMYF differentiation of luMCs through transforming growth factor-β signaling, thus regulating normal lung development.

Background: It was recently reported that expression of prospero homeobox protein-1 (PROX1) is correlated with the prognosis of esophageal cancer and colorectal cancer. However, its correlation with gastric cancer is unclear. Materials and Methods: Our study analyzed the effect of PROX1 knockdown on the migration, invasion and proliferation of the MKN45 human gastric cancer cell line. The correlation between PROX1 expression levels and clinicopathological factors were also analyzed in tumor samples from 99 patients with gastric cancer. Results: Migration, invasion and proliferation were significantly reduced in MKN45 cells with PROX1 knockdown. PROX1 expression was detected in gastric cancer tissues at various levels. PROX1 expression levels were positively correlated with cancer stage, N factor, lymphatic vascular invasion, and vascular invasion in patients with gastric cancer. Analysis of overall and recurrence-free survival indicated that high PROX1 expression was significantly correlated with poor prognosis. Conclusion: PROX1 can be an indicator of poor prognosis and a molecular target for gastric cancer treatment. In recent years, the treatment of cancer has greatly been advanced with the advent of molecular-targeted therapeutic agents. They have an inhibitory effect specifically on cancer cells, but relatively few side-effects compared with conventional anticancer agents. Among them, the progress in chemotherapy for advanced colorectal cancer is remarkable, and the advent of various therapeutic agents, for example, monoclonal antibodies against epidermal growth factor and against vascular endothelial growth factor (VEGF), is expected to improve prognosis. On the other hand, in the field of gastric cancer, trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer is the molecular-targeted therapeutic agent that has proven useful, to date. Ramucirumab, which is an antibody against VEGF receptor 2 has become an agent for second-line chemotherapy and is expected to have a therapeutic effect on gastric cancer. However, options for second-line or third-line therapy are fewer than those for colon cancer. Prospero homeobox protein-1 (PROX1) is a transcription regulator which has been implicated in differentiation of lymphatic endothelial cells (1). Previous studies showed that PROX1 expression levels are correlated with cancer progression and prognosis. For instance, high PROX1 expression in human colon and esophageal cancer tissues is correlated with poor prognosis (2, 3). Knockdown of PROX1 by siRNA treatment suppressed proliferation and migration in colon and esophageal cancer cell lines. On the other hand, PROX1 is reported to be a tumor suppressor in neuroblastoma, breast cancer, pancreatic cancer, and hepatocellular carcinoma (4-6). Based on these previous findings, the role of PROX1 in cancer progression or suppression is currently drawing attention, although its mechanism is not fully addressed. In this study, we examined the correlation of PROX1 expression levels with the migr...

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