Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

Hiraki, Akio; Ueoka, Hiroshi; Bessho, Akihiro; Segawa, Yoshihiko; Takigawa, Nagio; Kiura, Katsuyuki; Eguchi, Katsumi; Yoneda, Toshiyuki; Tanimoto, Mitsune; Harada, Mine

doi:10.1002/cncr.10828

Cited by 64 publications

(39 citation statements)

References 29 publications

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“…In Pthrp-ablated animals, primary tumor hyperplasia was considerably delayed, and palpable tumors appeared much later and were smaller and fewer than in control mice. Our observations are in agreement with several clinical studies in which patients with tumors produc- ing high PTHrP levels presented higher rates of metastasis and increased or earlier mortality (40)(41)(42)(43). A recent report reached opposite conclusions, but relied on animal models with a very late-onset oncogenic system (neu based), which is more relevant to tumors arising in older animals (44), and used mice with a heterogeneous genetic background.…”

Section: Discussionsupporting

confidence: 89%

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Li¹,

Karaplis²,

Huang³

et al. 2011

J. Clin. Invest.

114

118

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Parathyroid hormone-related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer -it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.

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Section: Discussionsupporting

confidence: 89%

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Li¹,

Karaplis²,

Huang³

et al. 2011

J. Clin. Invest.

114

118

View full text Add to dashboard Cite

show abstract

“…The studies in which PTHrP had a positive prognostic role in cancer used an antibody to PTHrP 1-14 for breast cancer, one directed against PTHrP 126-136 in renal cell carcinoma and our study (1,18,30). Furthermore, the small cell lung cancer case report and the NSCLC case series in which PTHrP apparently associated with more aggressive malignancies used NH 2 -terminal and COOH-terminal PTHrP antibodies, respectively (31,32). Thus, study results do not align based on PTHrP epitope.…”

Section: Discussionmentioning

confidence: 61%

“…We can state that tumor PTHrP 109-141 immunoreactivity was not linked to stage for the patients with non -small cell cancer in our study. Another study investigated survival of NSCLC patients with hypercalcemia (32). Seven patients with high serum levels of PTHrP, measured with a COOH-terminal PTHrP assay, had a median survival time of 1.4 months, whereas 16 patients with lower serum PTHrP survived a median time of 5.4 months.…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Survival Advantage with Parathyroid Hormone–Related Protein in Non–Small Cell Lung Carcinoma Patients

Hastings¹,

Laux²,

Casillas³

et al. 2006

Clinical Cancer Research

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Purpose: Parathyroid hormone^related protein (PTHrP) is commonly expressed in non^small cell lung carcinomas (NSCLC). Expression of the protein could have implications for progression of the disease because it regulates cancer cell growth, apoptosis, and angiogenesis. However, its relationship with survival has not been evaluated in a large-scale investigation. Experimental Design: PTHrP expression was assessed in paraffin-embedded tumor samples from 407 patients with NSCLC by immunohistochemistry. A pathologist unaware of the clinical history classified specimens as PTHrP positive or PTHrP negative. The log-rank test was used to compare survivals of PTHrP-positive and PTHrP-negative groups, and Cox regression was used to adjust for additional covariates.Results: Median survival was 55 versus 22 months (P < 0.001) in female patients with and without tumor PTHrP, respectively. Male survival was 38 months independent of PTHrP status. Stage, histology, age, and smoking history were also associated with increased longevity. PTHrP remained a significant predictor of survival for female patients after controlling for stage, histology, and age. Conclusions: In this study, PTHrP expression was associated with a survival advantage in female patients. Additional investigations must be done to ascertain whether the result is reproducible and independent of potential confounding covariates. Sex-dependent effects of PTHrP in lung cancer would open new avenues of research into the role of sex in cancer progression.Parathyroid hormone-related protein (PTHrP) was discovered as the factor responsible for hypercalcemia of malignancy. As the name implies, PTHrP shares structural similarities with PTH, specifically in the NH 2 -terminal 34 amino acids. Consequently, PTHrP 1-34 binds to the same receptor as PTH 1-34, the type 1 PTH/PTHrP receptor (PTH1R), and duplicates the effects of PTH 1-34 in tissues that bear the receptor, including causing hypercalcemia. Hypercalcemic effects are mediated through decreases in calcium excretion in kidney and increases in calcium release from bone. It is less widely appreciated that PTHrP also exerts effects direct effects on cancer cells that could be important in the pathology of malignancy.

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“…17 In lung cancer, PTHrP level was an independent indicator for bone metastases and patients' survival, 18 and its role in bone metastases has been established in animal models as well.…”

Section: 3mentioning

confidence: 99%

Over‐expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma

Yang

Hoang

Kubo

et al. 2007

Intl Journal of Cancer

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Osteosarcoma is the most common primary bone malignancy in children and is associated with rapid bone growth. Parathyroid hormone-related peptide (PTHrP) signaling via parathyroid hormone Type 1 receptor (PTHR1) is important for skeletal development and is involved in bone metastases in other tumors. The aim of this study was to investigate the status of PTHrP/PTHR1 and its possible role in osteosarcoma. In a preliminary screening, a higher level of PTHR1 mRNA, but not PTHrP, was found in 4 osteosarcoma xenografts as compared with 4 standard cell lines, or 5 patient derived cell lines (p < 0.05) using quantitative RT-PCR. It was therefore extended to 55 patient specimens, in which a significantly higher level of PTHR1 mRNA was detected in metastatic or relapsed samples than those from primary sites (p < 0.01). Cell behavior caused by PTHR1 overexpression was further studied in vitro using PTHR1 transfected HOS cell line as a model. Over-expression of PHTR1 resulted in increased proliferation, motility and Matrigel invasion without addition of exogenous PTHrP suggesting an autocrine effect. Importantly, the aggressiveness in PTHR1-expressing cells was completely reversed by RNAi mediated gene knockdown. In addition, PTHR1 overexpression led to delayed osteoblastic differentiation and upregulation of genes involved in extracellular matrix production, such as TGF-b1 and connective tissue growth factor. When cocultured with bone marrow derived monocytes, PTHR1 transfected HOS cells induced a greater number of osteoclasts. This study suggests that PTHR1 over-expression may promote osteosarcoma progression by conferring a more aggressive phenotype, and forming a more favorable microenvironment. ' 2007 Wiley-Liss, Inc.Key words: parathyroid hormone Type 1 receptor; metastasis; osteosarcoma Osteosarcoma is typically a high-grade malignancy that has a peak incidence in children and young adults. More than 75% of osteosarcoma in adolescents occurs near growing joints, such as the distal femur, proximal tibia and proximal humerus, implying an association with rapid bone growth.1 Osteosarcoma has a tendency to metastasize early. The 5-year event free survival of osteosarcoma has been improved dramatically from 10% to nearly 70% for patients without detectable metastases at initial diagnosis with the adoption of neo-adjuvant and adjuvant chemotherapy, which is aimed at eliminating microscopic metastatic disease and making primary tumor more amenable for limb salvage procedures. 2,3However, for patients with radiographically detectable metastases or relapse, cure is extremely difficult to achieve even using the regimens of intensified chemotherapy that have being explored during the past 2 decades.4,5 Therefore, identification of factors contributing to tumor progression and metastatic behavior will be essential to improve the outcome for patients with this disease.Parathyroid hormone Type 1 receptor (PTHR1) is the common receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP). PTH and PTHrP sha...

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Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

Cited by 64 publications

References 29 publications

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Sex-Specific Survival Advantage with Parathyroid Hormone–Related Protein in Non–Small Cell Lung Carcinoma Patients

Over‐expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma

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