Expression of parathyroid hormone-related protein in gastrointestinal malignancies
Parathyroid hormone-related protein (PTHrP) is a peptide hormone which, when abundantly produced by certain tumours, and released into the systemic circulation, stimulates via an endocrine-like pathway, bone resorption and renal calcium reabsorption, by interacting with a receptor that it shares with parathyroid hormone (PTH), the PTH/PTHrP type 1 receptor (PTH1R). PTHrP is undetectable in the circulation of normal subjects, but is produced in a paracrine/autocrine fashion during foetal and adult life by a number of normal cells and tissues, playing important roles in regulating cell proliferation, differentiation, and development. Tumours derived from the gastrointestinal tract that are not normally associated with hypercalcaemia, such as pancreatic adenocarcinoma, are known to express PTHrP. The expression of PTH1R has not been examined in pancreatic adenocarcinoma: there is no published literature detailing the evaluation of expression of PTHrP and PTH1R in gastrointestinal neuroendocrine tumours or hepatocellular carcinoma (HCC). PTHrP and PTH1R protein was found, utilising immunohistochemistry, to be expressed by tumour cells in the majority of cases of a series of resection specimens of pancreatic adenocarcinoma and gastrointestinal neuroendocrine tumours, and all HCC studied. Furthermore, PTHrP and PTH1R were detected by western immunoblotting of cell lysates, and by immunohistochemistry in cells, from tumour cell lines derived from the above tumour types. Immunohistochemical expression of PTHrP, PTH1R, and the cell proliferation marker Ki67 was assessed and scored in tissue from normal liver, cirrhotic liver, putative neoplastic precursor lesions macroregenerative (MRN) and dysplastic nodules (DN) , and HCCs. Immunopositivity for PTHrP correlated with the Ki67 score, and both sequentially increased from normal liver, to cirrhotic liver, to MRNs, to DNs, with a gradient of expression that peaked in tumour cells. Amino-terminal PTHrP (1-34) peptide was fluorescently labelled and observed to be taken up by HepG2 cells, confirming that these cells express functional PTH1R. The common expression of both PTHrP and PTH1R implies a possible autocrine/paracrine role for PTHrP/PTHIR in these tumours. The positive correlation in expression of PTHrP with Ki67, and sequential rise in the continuum of normal liver through to HCC, qualifies PTHrP as a likely candidate to influence hepatocyte and HCC growth. Agents that target the PTHrP/PTHIR system may have a therapeutic potential in these gastrointestinal malignancies that are frequently refractory to existing treatments.