Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

NOVOA DÍAZ BELEN; CARRIERE PEDRO MATÍAS; MARTIN, MARIA JULIA; CALVO, NATALIA; GENTILI, CLAUDIA

WORLD JOURNAL OF GASTROENTEROLOGY

W J G PRESS

Lugar: Beijing; Año: 2021 vol. 27 p. 7025 - 7040

1007-9327

Colorectal cancer (CRC) remains one of the leading causes of mortality frommalignant diseases worldwide. In general terms, CRC presents high heterogeneitydue to the influence of different genetic and environmental factors; also, theneoplastic cells are strongly influenced by the extracellular matrix and severalsurrounding cells, known together as the tumor microenvironment (TME).Bidirectional communication takes place between the tumor and the TME throughthe release of autocrine and paracrine factors. Parathyroid hormone-relatedpeptide (PTHrP) is a cytokine secreted by a wide variety of tissues and is able toregulate several cellular functions both in physiological as well as in pathologicalprocesses. It exerts its effects as a paracrine/autocrine factor, although its mode ofaction is mainly paracrine. It has been shown that this peptide is expressed byseveral tumors and that the tumor secretion of PTHrP is responsible for themalignant humoral hypercalcemia. Eight years ago, when our research groupstarted studying PTHrP effects in the experimental models derived from intestinaltumors, the literature available at the time addressing the effects of PTHrP oncolorectal tumors was limited, and no articles had been published regarding to theparacrine action of PTHrP in CRC cells. Based on this and on our previousfindings regarding the role of PTH in CRC cells, our purpose in recent years hasbeen to explore the role of PTHrP in CRC. We analyzed the behavior of CRC cellstreated with exogenous PTHrP, focalizing in the study of the following events:Survival, cell cycle progression and proliferation, migration, chemoresistance,tumor-associated angiogenesis, epithelial to mesenchymal transition program andother events also associated with invasion, such us the induction of cancer stemcells features. This work summarizes the major findings obtained by our investigationgroup using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressive phenotype of CRC cells andthe molecular mechanisms involved in these processes. Recently, we found thatthis cytokine induces this malignant behavior not only by its direct action on theseintestinal cells but also through its influence on cells derived from TME,promoting a communication between CRC cells and surrounding cells thatcontributes to the molecular and morphological changes observed in CRC cells.These investigations establish the basis for our next studies in order to address theclinical applicability of our findings. Recognizing the factors and mechanisms thatpromote invasion in CRC cells, evasion to the cytotoxic effects of current CRCtherapies and thus metastasis is decisive for the identification of new markerswith the potential to improve early diagnosis and/or to predict prognosis, topredetermine drug resistance and to provide treatment guidelines that includetargeted therapies for this disease.