Localised Collagen2a1 secretion supports lymphatic endothelial cell migration in the zebrafish embryo.

The lymphatic vasculature develops primarily from pre-existing veins. A pool of lymphatic endothelial cells (LECs) first sprouts from cardinal veins followed by migration and proliferation to colonise embryonic tissues. Although much is known about the molecular regulation of LEC fate and sprouting during early lymphangiogenesis, we know far less about the instructive and permissive signals that support LEC migration through the embryo. Using a forward genetic screen, we identified mbtps1 and sec23a, components of the COP-II protein secretory pathway, as essential for developmental lymphangiogenesis. In both mutants, LECs initially depart the cardinal vein but then fail in their ongoing migration. A key cargo that failed to be secreted in both mutants was a type II collagen (Col2a1). Col2a1 is normally secreted by notochord sheath cells, alongside which LECs migrate. col2a1a mutants displayed defects in the migratory behaviour of LECs and failed lymphangiogenesis. These studies thus identify Col2a1 as a key cargo secreted by notochord sheath cells and required for the migration of LECs. These findings combine with our current understanding to suggest that successive cell-to-cell and cell-matrix interactions regulate the migration of LECs through the embryonic environment during development.

Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk.

Lymphatic vascular development involves specification of lymphatic endothelial progenitors that subsequently undergo sprouting, proliferation and tissue growth to form a complex second vasculature. The Hippo pathway and effectors Yap and Taz control organ growth and regulate morphogenesis and cellular proliferation. Yap and Taz control angiogenesis but a role in lymphangiogenesis remains to be fully elucidated. Here we show that YAP displays dynamic changes in lymphatic progenitors and Yap1 is essential for lymphatic vascular development in zebrafish. Maternal and Zygotic (MZ) yap1 mutants show normal specification of lymphatic progenitors, abnormal cellular sprouting and reduced numbers of lymphatic progenitors emerging from the cardinal vein during lymphangiogenesis. Furthermore, Yap1 is indispensable for Vegfc-induced proliferation in a transgenic model of Vegfc overexpression. Paracrine Vegfc-signalling ultimately increases nuclear YAP in lymphatic progenitors to control lymphatic development. We thus identify a role for Yap in lymphangiogenesis, acting downstream of Vegfc to promote expansion of this vascular lineage.

IGF1R predicts better survival in high-grade serous epithelial ovarian cancer patients and correlates with hCtr1 levels.

Aim: To evaluate the potential of IGF1R as a prognostic marker for high-grade serous ovarian cancer (HGSOC) patients. Patients & methods: The expression levels of IGF1R and drug transporters (ABCB1, hCtr1) were measured longitudinally in chemo-naive and chemo-treated tumor samples from 19 HGSOC patients, and their correlation with the clinical outcome was examined. Results:IGF1R expression was significantly upregulated in treated tumor samples, which positively correlated with hCtr1 levels. Patients with metastatic tumors with IGF1R expression higher than median showed better overall survival (median not reached) and disease-free survival (26.7 months) than those with less than median expression (overall survival: 27.5 months [p = 0.029]; disease-free survival: 11.9 months [p = 0.014]). Conclusion: IGF1R prognosticates prolonged survival in HGSOC patients, possibly due to its positive correlation with hCtr1.

Molecular Imaging of Therapeutic Potential of Reporter Probes.

Success of medical treatments for any pathological disorders majorly depends on the efficacy of the therapeutic molecules and their delivery to the target sites. Non-invasive molecular imaging technologies have emerged as prime methods for validating both these aspects ranging from preclinical level to clinical application. Reporter genes and the respective reporter probes are essential components of molecular functional imaging that gained wide popularity throughout the world due to easy adaptation, user friendly software and cost-effective experiments. However, to monitor the therapeutic effects, reporter gene-reporter probes (RG-RP) are often combined with separate introductions of therapeutics whose delivery at target sites are not appropriately measured. A small group of reporter genes is associated with probes that behave like a signature as well as a therapeutic molecule thereby having theranostic properties. This Reporter Gene-Therapeutic Reporter Probe (RG-TRP) system bears additional advantages over RG-RP system and holds the promise of direct translational applications in humans. This short review focuses on describing the currently available and validated RG-TRP systems, delivery vehicles, associated imaging modalities, applications in various pathological conditions along with the merits and demerits. Identification of new RG-TRP system will open new direction in theranostic imaging with potential human applications.

IGF-1R inhibition potentiates cytotoxic effects of chemotherapeutic agents in early stages of chemoresistant ovarian cancer cells.

The kinetics and effect of hyper activated IGF-1R signaling is not well investigated during acquirement of platinum and taxol resistance in ovarian cancer cells. Herein we reported an upregulated IGF-1R expression in early stages of cisplatin paclitaxel and cisplatin-taxol resistance. Picropodophyllin, an IGF-1R inhibitor, alone and in combination with cisplatin, paclitaxel or both at lowest possible doses could reverse the resistance at early stages. Upregulated IGF-1R was also found in primary tumors of ovarian cancer patients after three to four cycles of platinum-taxol treatment. These findings indicate that a combination of cytotoxic agents and IGF-1R inhibitor is more effective at early stages of chemoresistant ovarian cancer.