Fibrosis is a characterized by excessive extracellular matrix deposition, resulting in tissue damage and loss of function. Activated fibroblasts are responsible for fibrotic phenotypes; however, the drivers of fibrosis are not fully understood. In this episode, Colin Jamora and Neha Pincha discuss their work, which shows that upregulation of plasminogen activator inhibitor type 1 (PAI1) on keratinocytes in mice with scleroderma-like disease promotes mast cell infiltration into the skin, subsequently increasing fibroblast activation and exacerbating fibrosis. The results of this study suggest that PAI1 should be further explored as a target for limiting fibrosis.
Macrophage polarization in response to stimuli within the microenvironment results in heterogeneous populations that can differentially influence disease. Atherosclerosis is largely inflammatory, with lipids driving polarization of M1 macrophages; however, alternatively activated, hemoglobin-scavenging CD163+ macrophages are present within atherosclerotic lesions and have been proposed to serve an antiinflammatory role. In this episode, Aloke Finn and Liang Guo discuss their work, which shows that CD163+ macrophages actually promote angiogenesis, vessel permeability, and leucocyte infiltration, thereby exacerbating plaque progression. The pathogenic effects of this alternatively activated population were driven by HIF1α/VEGF-A signaling, suggesting this pathway as a potential therapeutic target.
As primary tumor progression to metastasis dramatically increases mortality in patients with cancer, strategies to limit tumor cell growth and spread are of great interest. The orphan receptor tyrosine kinase Tie1 is highly expressed in intratumoral vasculature; however, the contribution of this receptor to tumor progression has not been defined. In this episode, Hellmut Augustin and Silvia La Porta, aided by original artwork by Carleen Spegg, discuss their work, which shows that loss of Tie1 in endothelial cells reduces primary tumor progression and limits metastasis. The results of this study indicate that Tie1 should be further explored as a therapeutic target for limiting cancer progression.
The combined efforts of Doug Lowy and John Schiller form the basis of the biology behind the vaccines for HPV (human papillomavirus), which underlies cervical cancers as well as oropharyngeal cancers. With widespread uptake, these vaccines have the potential to wipe out these cancers in a generation. The JCI spoke with Schiller and Lowy from the National Cancer Institute when they were in New York City to collect the 2017 Lasker~DeBakey Clinical Medical Research Award.
Melanoma-directed immunotherapies have improved quality of life and outcome for many patients with this malignancy. Unfortunately, treatment resistance develops in some individuals and other patients do not respond to therapy; therefore, there remains a need for additional intervention targets for this devastating disease. In this episode, Craig Ceol and Arvind Venkatesan discuss their recent study, which identifies GDF6-mediated BMP signaling as a driver of melanoma. Importantly, upregulation of this GDF6 in patients with melanoma associated with increased metastasis and decreased survival, supporting further development of strategies to target GDF6/BMP signaling.