January 31, 2021
Source: Cell Res. 2021 Jan;31(1):5-16. doi: 10.1038/s41422-020-0383-9. Epub 2020 Jul 30.
Authors: Jitka Fucikova , Radek Spisek , Guido Kroemer , Lorenzo Galluzzi
Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein involved in a spectrum of cellular processes. In healthy cells, CALR operates as a chaperone and Ca2+ buffer to assist correct protein folding within the ER. Besides favoring the maintenance of cellular proteostasis, these cell-intrinsic CALR functions support Ca2+-dependent processes, such as adhesion and integrin signaling, and ensure normal antigen presentation on MHC Class I molecules. Moreover, cancer cells succumbing to immunogenic cell death (ICD) expose CALR on their surface, which promotes the uptake of cell corpses by professional phagocytes and ultimately supports the initiation of anticancer immunity. Thus, loss-of-function CALR mutations promote oncogenesis not only as they impair cellular homeostasis in healthy cells, but also as they compromise natural and therapy-driven immunosurveillance. However, the prognostic impact of total or membrane-exposed CALR levels appears to vary considerably with cancer type. For instance, while genetic CALR defects promote pre-neoplastic myeloproliferation, patients with myeloproliferative neoplasms bearing CALR mutations often experience improved overall survival as compared to patients bearing wild-type CALR. Here, we discuss the context-dependent impact of CALR on malignant transformation, tumor progression and response to cancer therapy.
Conflict of interest statement
J.F. and R.S. are full-time employees of Sotio. G.K. has been holding research contracts with Bayer Healthcare, Genentech, Glaxo Smyth Kline, Institut Mérieux, Lytix Pharma, PharmaMar, Sotio and Vasculox. He is on the Board of Directors of the Bristol Myers Squibb Foundation France, member of the Scientific Advisory Board of The Longevity Labs, and scientific co-founder of everImmune, Samsara therapeutics and Therafast Bio. L.G. received research support from Lytix and Phosplatin, consulting fees from OmniSEQ, Astra Zeneca, Inzen and the Luke Heller TECPR2 Foundation, and he is member of Scientific Advisory Committees for Boehringer Ingelheim, The Longevity Labs and OmniSEQ.