The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer

Simple Summary Aside from its well-established role in prion disorders, in the last decades the significance of cellular prion protein (PrPC) expression in human cancers has attracted great attention. An extensive body of work provided evidence that PrPC contributes to tumorigenesis by regulating tumor growth, differentiation, and resistance to conventional therapies. In particular, PrPC over-expression has been related to the acquisition of a malignant phenotype of cancer stem cells (CSCs) in a variety of solid tumors, encompassing pancreatic ductal adenocarcinoma, osteosarcoma, breast, gastric, and colorectal cancers, and primary brain tumors as well. According to consensus, increased levels of PrPC endow CSCs with self-renewal, proliferative, migratory, and invasive capacities, along with increased resistance to anti-cancer agents. In addition, increasing evidence demonstrates that PrPc also participates in multi-protein complexes to modulate the oncogenic properties of CSCs, thus sustaining tumorigenesis. Therefore, strategies aimed at targeting PrPC and/or PrPC-organized complexes could be a promising approach for anti-cancer therapy. Abstract Cellular prion protein (PrPC) is seminal to modulate a variety of baseline cell functions to grant homeostasis. The classic role of such a protein was defined as a chaperone-like molecule being able to rescue cell survival. Nonetheless, PrPC also represents the precursor of the deleterious misfolded variant known as scrapie prion protein (PrPSc). This variant is detrimental in a variety of prion disorders. This multi-faceted role of PrP is greatly increased by recent findings showing how PrPC in its folded conformation may foster tumor progression by acting at multiple levels. The present review focuses on such a cancer-promoting effect. The manuscript analyzes recent findings on the occurrence of PrPC in various cancers and discusses the multiple effects, which sustain cancer progression. Within this frame, the effects of PrPC on stemness and differentiation are discussed. A special emphasis is provided on the spreading of PrPC and the epigenetic effects, which are induced in neighboring cells to activate cancer-related genes. These detrimental effects are further discussed in relation to the aberrancy of its physiological and beneficial role on cell homeostasis. A specific paragraph is dedicated to the role of PrPC beyond its effects in the biology of cancer to represent a potential biomarker in the follow up of patients following surgical resection.