Lung carcinoma progression and survival versus amino- and carboxyl-parathyroid hormone-related protein expression

Hastings, Randolph H.; Montgrain, Philippe R.; Quintana, Rick; Chobrutskiy, Boris I.; Davani, Ashkhan; Miyanohara, Atsushi; Mahooti, Sepi

doi:10.1007/s00432-017-2396-4

Cited by 5 publications

(5 citation statements)

References 30 publications

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“…In the past years, several authors have reported a correlation between the overexpression of PTHrP and tumor progression in lung, breast, and prostate cancers[ 16 , 21 , 60 ]. Our research group has shown that this cytokine also promotes the aggressive phenotype of intestinal tumor cells[ 13 , 24 - 26 ] .…”

Section: Resultsmentioning

confidence: 99%

Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide

Díaz¹,

Carriere²,

Gigola³

et al. 2022

WJG

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BACKGROUND Parathyroid hormone-related peptide (PTHrP) plays a key role in the development and progression of many tumors. We found that in colorectal cancer (CRC) HCT116 cells, the binding of PTHrP to its receptor PTHR type 1 (PTHR1) activates events associated with an aggressive phenotype. In HCT116 cell xenografts, PTHrP modulates the expression of molecular markers linked to tumor progression. Empirical evidence suggests that the Met receptor is involved in the development and evolution of CRC. Based on these data, we hypothesized that the signaling pathway trigged by PTHrP could be involved in the transactivation of Met and consequently in the aggressive behavior of CRC cells. AIM To elucidate the relationship among PTHR1, PTHrP, and Met in CRC models. METHODS For in vitro assays, HCT116 and Caco-2 cells derived from human CRC were incubated in the absence or presence of PTHrP (1-34) (10 -8 M). Where indicated, cells were pre-incubated with specific kinase inhibitors or dimethylsulfoxide, the vehicle of the inhibitors. The protein levels were evaluated by Western blot technique. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the changes in gene expression. Wound healing assay and morphological monitoring were performed to evaluate cell migration and changes related to the epithelial-mesenchymal transition (EMT), respectively. The number of viable HCT116 cells was counted by trypan blue dye exclusion test to evaluate the effects of irinotecan (CPT-11), oxaliplatin (OXA), or doxorubicin (DOXO) with or without PTHrP. For in vivo tests, HCT116 cell xenografts on 6-wk-old male N:NIH (S)_nu mice received daily intratumoral injections of PTHrP (40 μg/kg) in 100 μL phosphate-buffered saline (PBS) or the vehicle (PBS) as a control during 20 d. Humanitarian slaughter was carried out and the tumors were removed, weighed, and fixed in a 4% formaldehyde solution for subsequent treatment by immunoassays. To evaluate the expression of molecular markers in human tumor samples, we studied 23 specimens obtained from CRC patients which were treated at the Hospital Interzonal de Graves y Agudos Dr. José Penna (Bahía Blanca, Buenos Aires, Argentina) and the Hospital Provincial de Neuquén (Neuquén, Neuquén, Argentina) from January 1990 to December 2007. Seven cases with normal colorectal tissues were assigned to the control group. Tumor tissue samples and clinical histories of patients were analyzed. Paraffin-embedded blocks from primary tumors were reviewed by hematoxylin-eosin staining technique; subsequently, representative histological samples were selected from each patient. From each paraffin block, tumor sections were stained for immunohistochemical detection. The statistical significance of differences was analyzed using proper statistical analysis. The results were considered statistically significant at P < 0.0...

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Section: Resultsmentioning

confidence: 99%

Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide

Díaz¹,

Carriere²,

Gigola³

et al. 2022

WJG

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“…Elevated serum levels of PTHrP were correlated with an increased frequency of bone metastases and shorter survival in lung carcinoma patients with hypercalcemia ( n = 23) 35 . Interestingly, carboxyl terminal PTHrP peptide was described as a positive prognostic indicator for survival in female patients with NSCLC while amino terminal PTHrP peptide, which can stimulate thermogenic gene expression and induce cachexia, was found to be a negative survival factor in lung adenocarcinoma 13,36 . While negative influence of high PTHLH mRNA on overall survival of the patients may depend on potential oncogenic effects driven by PTHrP protein, 37 it is possible that PTHrP‐associated cancer cachexia may contribute to the worse outcome.…”

Section: Discussionmentioning

confidence: 99%

“… 35 Interestingly, carboxyl terminal PTHrP peptide was described as a positive prognostic indicator for survival in female patients with NSCLC while amino terminal PTHrP peptide, which can stimulate thermogenic gene expression and induce cachexia, was found to be a negative survival factor in lung adenocarcinoma. 13 , 36 While negative influence of high PTHLH mRNA on overall survival of the patients may depend on potential oncogenic effects driven by PTHrP protein, 37 it is possible that PTHrP‐associated cancer cachexia may contribute to the worse outcome. Our findings argue that EGFR signalling regulates PTHrP expression in tumours, thus the cachectic effects of PTHrP may be pronounced in patients with EGFR active tumours.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of epidermal growth factor receptor suppresses parathyroid hormone‐related protein expression in tumours and ameliorates cancer‐associated cachexia

Weber

Agca

Domaniku

et al. 2022

J cachexia sarcopenia muscle

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Background Lung cancer is the primary cause of cancer deaths worldwide. Activation of epidermal growth factor receptor (EGFR) leads to lung cancer progression and poor prognosis while involuntary weight loss remains a major problem. Tumour-derived parathyroid hormone-related protein (PTHrP) emerged as a potential mediator of cachexia. Here, we investigated the modulatory role of EGFR signalling in PTHrP (encoded by Pthlh) gene expression and the impact of this relationship on cancer cachexia. Methods Global gene expression profiles of Lewis lung carcinoma (LLC) cells were analysed. Pthlh mRNA levels were measured by qRT-PCR in LLC cells treated with EGFR ligands and tyrosine kinase inhibitors (TKIs). LLC tumour-bearing mice received EGFR TKI erlotinib for 7 days via intraperitoneal injection or oral gavage. Tumour Pthlh mRNA, weight of fat/muscle tissue, and grip strength were assessed. RNA-seq data from The Cancer Genome Atlas and gene expression analysis tools were used to characterize expression profiles of PTHLH and EGFR along with correlation analysis of PTHLH with EGFR and transforming growth factor alpha (TGFA) in human lung cancer and head and neck squamous carcinoma (HNSC). Survival of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with EGFR gene alterations was analysed in regard to PTHLH expression. Results Expression of EGFR ligands, EGFR itself, and PTHrP co-clusters in LLC cells. Activation of EGFR signalling with its ligands significantly increases (3.8-fold, P < 0.0005) while EGFR TKIs significantly decrease (90%, P < 0.0005) Pthlh mRNA levels in LLC cells. Pthlh mRNA drops 65-75% (P < 0.0005) in tumours upon treatment of LLC tumour-bearing mice with erlotinib while their muscle mass and grip strength increase (9.2% P < 0.05, 23% P < 0.005, respectively) compared with tumour-bearing control mice. PTHLH is overexpressed in tumours of LUSC (45.8-fold, P < 0.05) and HNSC (17.5-fold, P < 0.05) compared with normal tissue. PTHLH expression correlates with EGFR and its ligand TGFA in both cancers (LUSC: n = 745, R = 0.32, P < 0.0001 and R = 0.51, P < 0.0001; HNSC: n = 545, R = 0.34, P < 0.001 and R = 0.50, P < 0.001, respectively). High PTHLH mRNA associates with poor overall survival in LUAD patients with activating EGFR mutations (n = 40, log-rank test, P = 0.0451). Conclusions Epidermal growth factor receptor signalling regulates expression of cachexia mediator PTHrP. EGFR inhibition reduces PTHrP expression in LLC tumours and ameliorates cachexia in LLC tumour-bearing mice.

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“…In this regard, it is noteworthy that different tissues or malignancies have specific and different post-translational processing, producing different proportions of daughter peptides from the three PTHrP isoforms, leading to prevalent paracrine, autocrine, or intracrine effects [ 6 , 49 ]. In fact, in lung carcinoma, the expression of amino and carboxyl regions of PTHrP can vary independently in different tumor cases, so that the presence of amino PTHrP and PTH1R worsen the prognosis in lung cancer patients [ 32 ], while, carboxyl PTHrP, when present, may lower the stimulatory effect of amino PTHrP [ 50 ]. Moreover, many evidences indicate that discrete PTHrP fragments exert multiple effects on different neoplastic cell populations via cytosolic and nuclear targets, by functioning in different settings either as inducers of cell proliferation or leading to cell death and apoptosis [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor type 1 in locally advanced laryngeal cancer as prognostic indicators of relapse and survival

et al. 2022

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Background Parathyroid hormone-related peptide (PTHrP) overexpression and poor patient outcome have been reported for many human tumors, but no studies are available in laryngeal cancer. Therefore, we studied the expression of PTHrP and its receptor, parathyroid hormone-related peptide receptor type 1 (PTH1R), in primary locally advanced laryngeal squamous cell carcinomas (LALSCC) also in relation to the clinical outcome of patients. Methods We conducted a retrospective exploratory study, using immunohistochemistry, on PTHrP, PTH1R and HER1 expressions in LALSCC of 66 patients treated with bio-radiotherapy with cetuximab. Results The expressions of PTHrP and PTH1R in LALSCC were associated with the degree of tumor differentiation (p = 0.01 and 0.04, respectively). Poorly differentiated tumors, with worse prognosis, expressed PTHrP at nuclear level and were PTH1R negative. PTHrP and PTH1R were expressed at cytoplasmic level in normal larynx epithelium and more differentiated laryngeal cancer cells, suggesting an autocrine/paracrine role of PTHrP in squamous cell differentiation of well differentiated tumors with good prognosis. Eighty-one percent HER1 positive tumors expressed PTHrP (p < 0.0001), mainly at nuclear level, consistent with the known up-regulation of PTHrP gene by HER1 signaling. In multivariable analyses, patients with PTHrP positive tumors had a higher relative risk of relapse (HR = 5.49; CI 95% = 1.62–22.24; p = 0.006) and survival (HR = 8.21; CI 95% = 1.19–105.00; p = 0.031) while those with PTH1R positive tumors showed a lower relative risk of relapse (HR = 0.18; CI 95% = 0.04–0.62; p = 0.002) and survival (HR = 0.18; CI 95% = 0.04–0.91; p = 0.029). Conclusions In LALSCC nuclear PTHrP and absence of PTH1R expressions could be useful in predicting response and/or resistance to cetuximab in combined therapies, contributing to an aggressive behavior of tumor cells downstream to HER1.

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Lung carcinoma progression and survival versus amino- and carboxyl-parathyroid hormone-related protein expression

Abstract: Amino PTHrP and carboxyl PTHrP can vary independently in different lung carcinomas. Carboxyl PTHrP may temper the stimulatory effect of amino PTHrP on cancer progression.

Cited by 5 publications

References 30 publications

Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide

Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide

Inhibition of epidermal growth factor receptor suppresses parathyroid hormone‐related protein expression in tumours and ameliorates cancer‐associated cachexia

Parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor type 1 in locally advanced laryngeal cancer as prognostic indicators of relapse and survival

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