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

Cellular prion protein (PrP^C) 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, PrP^C also represents the precursor of the deleterious misfolded variant known as scrapie prion protein (PrP^Sc). This variant is detrimental in a variety of prion disorders. This multi-faceted role of PrP is greatly increased by recent findings showing how PrP^C 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 PrP^C in various cancers and discusses the multiple effects, which sustain cancer progression. Within this frame, the effects of PrP^C on stemness and differentiation are discussed. A special emphasis is provided on the spreading of PrP^C 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 PrP^C beyond its effects in the biology of cancer to represent a potential biomarker in the follow up of patients following surgical resection.