Inflammation Research Network-Snyder Institute for Chronic Disease, Departments of Physiology and Pharmacology and Medicine, University of Calgary Cumming School of Medicine, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1416753955, Iran.
Biol Chem. 2018 Sep 25;399(9):1023-1039. doi: 10.1515/hsz-2018-0001.
We propose that in the microenvironment of inflammatory tissues, including tumours, extracellular proteinases can modulate cell signalling in part by regulating proteinase-activated receptors (PARs). We have been exploring this mechanism in a variety of inflammation and tumour-related settings that include tumour-derived cultured cells from prostate and bladder cancer, as well as immune inflammatory cells that are involved in the pathology of inflammatory diseases including multiple sclerosis. Our work showed that proteinase signalling via the PARs affects prostate and bladder cancer-derived tumour cell behaviour and can regulate calcium signalling in human T-cell and macrophage-related inflammatory cells as well as in murine splenocytes. Further, we found that the tumour-derived prostate cancer cells and immune-related cells (Jurkat, THP1, mouse splenocytes) can produce PAR-regulating proteinases (including kallikreins: kallikrein-related peptidases), that can control tissue function by both a paracrine and autocrine mechanism. We suggest that this PAR-driven signalling process involving secreted microenvironment proteinases can play a key role in cancer and inflammatory diseases including multiple sclerosis.
我们提出，在包括肿瘤在内的炎症组织的微环境中，细胞外蛋白酶可以通过调节蛋白酶激活受体（PAR）来调节细胞信号转导。我们一直在多种炎症和肿瘤相关的环境中探索这种机制，包括来自前列腺癌和膀胱癌的肿瘤衍生培养细胞，以及参与包括多发性硬化症在内的炎症性疾病病理学的免疫炎症细胞。我们的工作表明，通过 PAR 的蛋白酶信号转导会影响前列腺癌和膀胱癌衍生的肿瘤细胞行为，并可以调节人 T 细胞和巨噬细胞相关炎症细胞以及鼠脾细胞中的钙信号转导。此外，我们发现肿瘤衍生的前列腺癌细胞和免疫相关细胞（Jurkat、THP1、鼠脾细胞）可以产生调节 PAR 的蛋白酶（包括激肽释放酶：激肽释放酶相关肽酶），可以通过旁分泌和自分泌机制控制组织功能。我们认为，这种涉及分泌的微环境蛋白酶的 PAR 驱动的信号转导过程可能在癌症和炎症性疾病（包括多发性硬化症）中发挥关键作用。
