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World J Gastroenterol. Nov 7, 2021; 27(41): 7025-7040
Published online Nov 7, 2021. doi: 10.3748/wjg.v27.i41.7025
Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells
María Belén Novoa Díaz, Pedro Matías Carriere, María Julia Martín, Natalia Calvo, Claudia Gentili
María Belén Novoa Díaz, Pedro Matías Carriere, María Julia Martín, Natalia Calvo, Claudia Gentili, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
María Julia Martín, Departamento de Química, Universidad Nacional del Sur (UNS)- INQUISUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
Author contributions: Calvo N and Gentili C supervised this project; Gentili C was responsible for the project administration and funding acquisition and provided the resources; All authors were involved in conceptualization, methodology, investigation, formal analysis, visualization, writing original draft, writing-review and editing.
Supported by Agencia Nacional de Promoción Científica y Tecnológica, No. PICT-2013-1441; Consejo Nacional de Investigaciones Científicas y Técnicas, No. PIP11220150100350; Instituto Nacional del Cáncer, Asistencia financiera II, No. 12002-4395-14-1; Instituto Nacional del Cáncer, Asistencia Financiera III, No. RESOL-2016-1006-E-APN-MS; and Universidad Nacional del Sur, Argentina, No. PGI: 24/B230; PGI: 24/B303.
Conflict-of-interest statement: Authors declare no conflict of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Claudia Gentili, PhD, Professor, Research Scientist, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), San Juan 670, Bahía Blanca 8000, Buenos Aires, Argentina. cgentili@criba.edu.ar
Received: April 27, 2021
Peer-review started: April 27, 2021
First decision: June 13, 2021
Revised: June 14, 2021
Accepted: August 23, 2021
Article in press: August 23, 2021
Published online: November 7, 2021
Processing time: 192 Days and 8.8 Hours
Abstract

Colorectal cancer (CRC) remains one of the leading causes of mortality from malignant diseases worldwide. In general terms, CRC presents high heterogeneity due to the influence of different genetic and environmental factors; also, the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells, known together as the tumor microenvironment (TME). Bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine factors. Parathyroid hormone-related peptide (PTHrP) is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological processes. It exerts its effects as a paracrine/autocrine factor, although its mode of action is mainly paracrine. It has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral hypercalcemia. Eight years ago, when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors, the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited, and no articles had been published regarding to the paracrine action of PTHrP in CRC cells. Based on this and on our previous findings regarding the role of PTH in CRC cells, our purpose in recent years has been to explore the role of PTHrP in CRC. We analyzed the behavior of CRC cells treated 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 and other events also associated with invasion, such us the induction of cancer stem cells features. This work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressive phenotype of CRC cells and the molecular mechanisms involved in these processes. Recently, we found that this cytokine induces this malignant behavior not only by its direct action on these intestinal cells but also through its influence on cells derived from TME, promoting a communication between CRC cells and surrounding cells that contributes to the molecular and morphological changes observed in CRC cells. These investigations establish the basis for our next studies in order to address the clinical applicability of our findings. Recognizing the factors and mechanisms that promote invasion in CRC cells, evasion to the cytotoxic effects of current CRC therapies and thus metastasis is decisive for the identification of new markers with the potential to improve early diagnosis and/or to predict prognosis, to predetermine drug resistance and to provide treatment guidelines that include targeted therapies for this disease.

Keywords: Parathyroid hormone-related protein; Colorectal cancer; Tumor biomarkers; Neoplastic processes; Drug resistance; Tumor microenvironment

Core Tip: In colorectal cancer (CRC) cells, we found that parathyroid hormone-related peptide (PTHrP) promotes survival, cell cycle progression, proliferation, migration and chemoresistance and also modulates markers expression associated with invasion, angiogenesis, epithelial to mesenchymal transition and cancer stem cells features. In vivo tests indicate that PTHrP administration increases the expression of several markers related to tumorigenic events. Recently, we observed that PTHrP influences on tumor microenvironment cells, inducing events associated with the progression of CRC. Our project focuses in understanding the biology of CRC and the underlying mechanisms related to the aggressive behavior of CRC cells with the aim to identify new markers that improve the diagnosis, prognosis and therapy of CRC.