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

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

Figure 1

Comparison between protein structure of parathyroid hormone-related peptide and parathyroid hormone. Parathyroid hormone-related peptide (PTHrP) peptide (left side) undergoes a complex post-translational process, obtaining several secreted forms. The N-terminal region 1-34 (green) shows high homology with parathyroid hormone (PTH) and shares more than 60% of the first 13 amino acids (first vertical line). This region allows PTHrP to interact with the type 1 PTH receptor. The PTHrP 36-86, region between N-terminal domain and the second vertical line, is related to placental calcium transport. The 87-107 domain contains a nuclear localization signal (domain between the second and third vertical lines), and the remaining COOH region corresponds to the osteostatin domain[20,24,25]. This figure is original for this work and is based on data published in Soki et al[20], Wysolmerski JJ[24] and Goltzman D[25].

Figure 2

Molecular mechanisms involved in parathyroid hormone-related peptide effects on colorectal cancer cells. Parathyroid hormone-related peptide (PTHrP) induces cell cycle progression and proliferation of colorectal cancer (CRC) cells through non-receptor tyrosine kinase Src (Src), extracellular signal-regulated kinase (ERK) 1/2 and p38, both members of the mitogen activated protein kinases family (MAPK), PI3K/protein kinase B (Akt), p90 ribosomal S6 kinase (RSK) and β-catenin pathways. This cytokine also promotes CRC cell migration and focal adhesion kinase (FAK) protein expression through ERK/RSK signaling pathway[37-40]. This figure is original for this work and shows the results published in Calvo et al[37], Martín et al[38], Martín et al[39], and Calvo et al[40]. ATF-1: Activating transcription factor 1; CREB: cAMP response element binding protein; PI3K: Phosphoinositide 3-kinase;PKC: Protein kinase C; PTHR1: Parathyroid hormone receptor 1.

Figure 3

Events that promote an aggressive phenotype on colorectal cancer cells and are related to chemotherapeutic drug resistance and treatment failure. CRC: Colorectal cancer; CSC: Cancer stem cell; EMT: Epithelial to mesenchymal transition.

Figure 4

Parathyroid hormone-related peptide induces tumor-associated angiogenesis through the pro-angiogenic factor vascular endothelial growth factor released from colorectal cancer cells. This figure is original for this work and shows results published in Calvo et al[44]. PTHrP: Parathyroid hormone-related peptide; VEGF: Vascular endothelial growth factor.

Figure 5

Parathyroid hormone-related peptide establishes a communication between colorectal cancer cells and endothelial HMEC cells through molecular factors modulating markers expression and morphological changes associated with cellular programs that promote the invasive phenotype in HCT116 cells. This figure is original for this work and shows results published in Carriere et al[45]. EMT: Epithelial to mesenchymal transition; PTHrP: Parathyroid hormone-related peptide.