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Lichtenstein AV. Rethinking the Evolutionary Origin, Function, and Treatment of Cancer. BIOCHEMISTRY. BIOKHIMIIA 2025; 90:19-31. [PMID: 40058971 DOI: 10.1134/s0006297924603575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 09/29/2024] [Accepted: 12/08/2024] [Indexed: 05/13/2025]
Abstract
Despite remarkable progress in basic oncology, practical results remain unsatisfactory. This discrepancy is partly due to the exclusive focus on processes within the cancer cell, which results in a lack of recognition of cancer as a systemic disease. It is evident that a wise balance is needed between two alternative methodological approaches: reductionism, which would break down complex phenomena into smaller units to be studied separately, and holism, which emphasizes the study of complex systems as integrated wholes. A consistent holistic approach has so far led to the notion of cancer as a special organ, stimulating debate about its function and evolutionary significance. This article discusses the role of cancer as a mechanism of purifying selection of the gene pool, the correlation between hereditary and sporadic cancer, the cancer interactome, and the role of metastasis in a lethal outcome. It is also proposed that neutralizing the cancer interactome may be a novel treatment strategy.
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Affiliation(s)
- Anatoly V Lichtenstein
- N. N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of the Russian Federation, Moscow, 115478, Russia.
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Lee EJ, Lee KJ, Jung S, Park KH, Park SI. Mobilization of monocytic myeloid-derived suppressor cells is regulated by PTH1R activation in bone marrow stromal cells. Bone Res 2023; 11:22. [PMID: 37085481 PMCID: PMC10121701 DOI: 10.1038/s41413-023-00255-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 01/23/2023] [Accepted: 03/01/2023] [Indexed: 04/23/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are bone marrow (BM)-derived immunosuppressive cells in the tumor microenvironment, but the mechanism of MDSC mobilization from the BM remains unclear. We investigated how BM stromal cell activation by PTH1R contributes to MDSC mobilization. PTH1R activation by parathyroid hormone (PTH) or PTH-related peptide (PTHrP), a tumor-derived counterpart, mobilized monocytic (M-) MDSCs from murine BM without increasing immunosuppressive activity. In vitro cell-binding assays demonstrated that α4β1 integrin and vascular cell adhesion molecule (VCAM)-1, expressed on M-MDSCs and osteoblasts, respectively, are key to M-MDSC binding to osteoblasts. Upon PTH1R activation, osteoblasts express VEGF-A and IL6, leading to Src family kinase phosphorylation in M-MDSCs. Src inhibitors suppressed PTHrP-induced MDSC mobilization, and Src activation in M-MDSCs upregulated two proteases, ADAM-17 and MMP7, leading to VCAM1 shedding and subsequent disruption of M-MDSC tethering to osteoblasts. Collectively, our data provide the molecular mechanism of M-MDSC mobilization in the bones of tumor hosts.
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Affiliation(s)
- Eun Jung Lee
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
- The BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
| | - Kyoung Jin Lee
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
- The BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
| | - Seungpil Jung
- Division of Breast and Endocrine Surgery, Department of Surgery, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Kyong Hwa Park
- Division of Oncology and Hematology, Department of Internal Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Serk In Park
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea.
- The BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea.
- Vanderbilt Center for Bone Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
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Bone Metastasis of Breast Cancer: Molecular Mechanisms and Therapeutic Strategies. Cancers (Basel) 2022; 14:cancers14235727. [PMID: 36497209 PMCID: PMC9738274 DOI: 10.3390/cancers14235727] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/07/2022] [Accepted: 11/17/2022] [Indexed: 11/24/2022] Open
Abstract
Bone metastasis is a common complication of many types of advanced cancer, including breast cancer. Bone metastasis may cause severe pain, fractures, and hypercalcemia, rendering clinical management challenging and substantially reducing the quality of life and overall survival (OS) time of breast cancer patients. Studies have revealed that bone metastasis is related to interactions between tumor cells and the bone microenvironment, and involves complex molecular biological mechanisms, including colonization, osteolytic destruction, and an immunosuppressive bone microenvironment. Agents inhibiting bone metastasis (such as bisphosphate and denosumab) alleviate bone destruction and improve the quality of life of breast cancer patients with bone metastasis. However, the prognosis of these patients remains poor, and the specific biological mechanism of bone metastasis is incompletely understood. Additional basic and clinical studies are urgently needed, to further explore the mechanism of bone metastasis and develop new therapeutic drugs. This review presents a summary of the molecular mechanisms and therapeutic strategies of bone metastasis of breast cancer, aiming to improve the quality of life and prognosis of breast cancer patients and provide a reference for future research directions.
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Affiliation(s)
- Theresa A Guise
- From the Section of Bone and Mineral Disorders, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M.D. Anderson Cancer Center, and the Lawrence Bone Disease Program of Texas, Houston, and the Cancer Prevention Research Institute of Texas, Austin (T.A.G.); and the Section of Endocrinology and Metabolism, Department of Medicine, Yale School of Medicine, New Haven, CT (J.J.W.)
| | - John J Wysolmerski
- From the Section of Bone and Mineral Disorders, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M.D. Anderson Cancer Center, and the Lawrence Bone Disease Program of Texas, Houston, and the Cancer Prevention Research Institute of Texas, Austin (T.A.G.); and the Section of Endocrinology and Metabolism, Department of Medicine, Yale School of Medicine, New Haven, CT (J.J.W.)
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Ganesh M, Baim S. Hypercalcemia of Malignancy in a Case of Peripheral Nerve Sheath Tumor: Elucidating the Roles of Simultaneous Mechanisms. AACE Clin Case Rep 2020; 6:e135-e140. [DOI: 10.4158/accr-2019-0567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 01/30/2020] [Indexed: 11/15/2022] Open
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Xiong W, Zhao Y, Xiong Y, Xu M, Pudasaini B, Du H, Guo X. Coagulation factor IV is an indicator of symptomatic pulmonary embolism in patients with primary lung cancer. CLINICAL RESPIRATORY JOURNAL 2019; 14:124-131. [PMID: 31747482 DOI: 10.1111/crj.13109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 11/14/2019] [Accepted: 11/15/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Wei Xiong
- Department of Respiratory Medicine Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine Shanghai China
| | - Yunfeng Zhao
- Department of Respiratory Medicine Punan Hospital, Pudong New District Shanghai China
| | - Yifan Xiong
- Shanghai Jincai North Secondary School Shanghai China
| | - Mei Xu
- Department of Pediatrics Community Health Service Center of North Bund Shanghai China
| | - Bigyan Pudasaini
- Department of Internal Medicine Columbia Bainuo Clinic Shanghai China
| | - He Du
- Shanghai Pulmonary Hospital Affiliated to Tongji University School of Medicine Shanghai China
| | - Xuejun Guo
- Department of Respiratory Medicine Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine Shanghai China
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Cheloha RW, Gellman SH, Vilardaga JP, Gardella TJ. PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 2015; 11:712-24. [PMID: 26303600 PMCID: PMC4651712 DOI: 10.1038/nrendo.2015.139] [Citation(s) in RCA: 174] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHrP type 1 receptor; commonly known as PTHR1) is a family B G-protein-coupled receptor (GPCR) that regulates skeletal development, bone turnover and mineral ion homeostasis. PTHR1 transduces stimuli from PTH and PTHrP into the interior of target cells to promote diverse biochemical responses. Evaluation of the signalling properties of structurally modified PTHR1 ligands has helped to elucidate determinants of receptor function and mechanisms of downstream cellular and physiological responses. Analysis of PTHR1 responses induced by structurally modified ligands suggests that PTHR1 can continue to signal through a G-protein-mediated pathway within endosomes. Such findings challenge the longstanding paradigm in GPCR biology that the receptor is transiently activated at the cell membrane, followed by rapid deactivation and receptor internalization. Evaluation of structurally modified PTHR1 ligands has further led to the identification of ligand analogues that differ from PTH or PTHrP in the type, strength and duration of responses induced at the receptor, cellular and organism levels. These modified ligands, and the biochemical principles revealed through their use, might facilitate an improved understanding of PTHR1 function in vivo and enable the treatment of disorders resulting from defects in PTHR1 signalling. This Review discusses current understanding of PTHR1 modes of action and how these findings might be applied in future therapeutic agents.
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Affiliation(s)
- Ross W Cheloha
- Department of Chemistry, 1101 University Avenue, University of Wisconsin, Madison, WI 53706, USA
| | - Samuel H Gellman
- Department of Chemistry, 1101 University Avenue, University of Wisconsin, Madison, WI 53706, USA
| | - Jean-Pierre Vilardaga
- Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Thomas J Gardella
- Endocrine Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA
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Giri D, Ramakrishnan R, Hayden J, Brook L, Das U, Mughal MZ, Selby P, Dharmaraj P, Senniappan S. Denosumab Therapy for Refractory Hypercalcemia Secondary to Squamous Cell Carcinoma of Skin in Epidermolysis Bullosa. World J Oncol 2015; 6:345-348. [PMID: 29147430 PMCID: PMC5649725 DOI: 10.14740/wjon907w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2015] [Indexed: 11/18/2022] Open
Abstract
Hypercalcemia secondary to malignancy is rare in children and the majority is caused by tumor-produced parathyroid hormone-related protein (PTHrP). We report a case of hypercalcemia refractory to bisphosphonate and corticosteroid therapy, but responsive to denosumab. A 17-year-old boy with epidermolysis bullosa (EB) and advanced squamous cell carcinoma (SCC) of the left leg was referred with severe hypercalcemia (serum calcium, 4.2 mmol/L). The serum parathyroid hormone (PTH) was 0.7 pmol/L (1.1 - 6.9 pmol/L). The hypercalcemia was initially managed with hyperhydration, prednisolone and pamidronate. Following two infusions of pamidronate (1 mg/kg/dose), serum calcium fell to 2.87 mmol/L. However the hypercalcemia relapsed within a week (serum calcium, 3.61 mmol/L) needing aggressive management with intravenous fluids, prednisolone and two further doses of pamidronate. The serum calcium fell to 2.58 mmol/L over the first 4 days, but rose to 3.39 mmol/L 3 days later. As the hypercalcemia was refractory to bisphosphonate treatment, a trial dose of subcutaneous denosumab (60 mg) was administered following which the calcium fell to 2.86 mmol/L within 24 h and normocalcemia was sustained 4 days later. We report a case of refractory hypercalcemia secondary to malignant SCC, which responded well to denosumab therapy. To our knowledge, this is the first case of hypercalcemia of malignancy in an adolescent managed with denosumab.
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Affiliation(s)
- Dinesh Giri
- Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool L12 2AP, UK
| | - Renuka Ramakrishnan
- Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool L12 2AP, UK
| | - James Hayden
- Department of Paediatric Oncology, Alder Hey Children's Hospital, Liverpool L12 2AP, UK
| | - Lynda Brook
- Department of Paediatric Palliative Care, Alder Hey Children's Hospital, Liverpool L12 2AP, UK
| | - Urmi Das
- Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool L12 2AP, UK
| | - M Zulf Mughal
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Oxford Rd, Manchester M13 9WL, UK
| | - Peter Selby
- Department of Medicine, Manchester Royal Infirmary, Manchester M139WL, UK
| | - Poonam Dharmaraj
- Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.,The authors contributed equally to this manuscript
| | - Senthil Senniappan
- Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.,The authors contributed equally to this manuscript
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Cholangiocarcinoma presenting with hypercalcemia and thrombocytopenia. Case Rep Med 2014; 2014:246817. [PMID: 25024705 PMCID: PMC4082921 DOI: 10.1155/2014/246817] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 05/25/2014] [Accepted: 05/26/2014] [Indexed: 11/17/2022] Open
Abstract
Malignant hypercalcemia and thrombocytopenia may result from bone metastasis of cholangiocarcinoma (CC). Our case was 53-year-old man admitted to emergency department with symptoms of anorexia, weight loss, nausea, vomiting, and general fatigue in February 2012. His laboratory findings showed hypercalcemia and thrombocytopenia. CT showed a large multinodular mass in the right lobe and, extending through left lobe of the liver. We considered the diagnosis of hypercalcemia of malignancy with elevated calcium levels and suppressed PTH level with the existence of skeletal bone metastasis and the absence of parathyroid gland pathology. Treatment of hypercalcemia with IV saline, furosemide, and calcitonin improved the patient symptoms. After the 8th day of admission, calcium level, thrombocytopenia, and other symptoms were normalized. Patient was sustained surgically inoperable and transferred to medical oncology department for the purpose of palliative chemotherapy and intended radiotherapy for bone metastasis. Hypercalcemia relapsed 4 weeks after discharge and patient died at the 5th month after admission due to disseminated metastasis. We should be aware of CC with symptomatic hypercalcemia and rarely low platelet count. The correction of hypercalcemia provides symptomatic relief and stability of patients.
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Polly P, Tan TC. The role of vitamin D in skeletal and cardiac muscle function. Front Physiol 2014; 5:145. [PMID: 24782788 PMCID: PMC3995052 DOI: 10.3389/fphys.2014.00145] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 03/27/2014] [Indexed: 12/17/2022] Open
Abstract
Myopathy is a feature of many inflammatory syndromes. Chronic inflammation has been linked to pathophysiological mechanisms which implicate 1,25 dihydroxyvitamin D3 (1,25-(OH)2D3)-mediated signaling pathways with emerging evidence supporting a role for the vitamin D receptor (VDR) in contractile and metabolic function of both skeletal and cardiac muscle. Altered VDR expression in skeletal and cardiac muscle has been reported to result in significant effects on metabolism, calcium signaling and fibrosis in these tissues. Elevated levels of serum inflammatory cytokines, such as IL-6, TNF-α and IFNγ, have been shown to impact myogenic and nuclear receptor signaling pathways in cancer-induced cachexia. The dysregulation of nuclear receptors, such as VDR and RXRα in muscle cells, has also been postulated to result in myopathy via their effects on muscle structural integrity and metabolism. Future research directions include generating transcriptome-wide information incorporating VDR and its gene targets and using systems biology approaches to identify altered molecular networks in human tissues such as muscle. These approaches will aid in the development of novel therapeutic targeting strategies for inflammation-induced myopathies.
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Affiliation(s)
- Patsie Polly
- Inflammation and Infection Research Centre, School of Medical Sciences, Faculty of Medicine, UNSW Australia Kensington, NSW, Australia ; Department of Pathology, School of Medical Sciences, Faculty of Medicine, UNSW Australia Kensington, NSW, Australia
| | - Timothy C Tan
- Inflammation and Infection Research Centre, School of Medical Sciences, Faculty of Medicine, UNSW Australia Kensington, NSW, Australia ; Cardiac Ultrasound Laboratory, Department of Cardiology, Massachusetts General Hospital Boston, MA, USA
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Les hypercalcémies malignes: étude rétrospective sur 150 patients. ONCOLOGIE 2014. [DOI: 10.1007/s10269-014-2385-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Wright LE, Guise TA. The Role of PTHrP in Skeletal Metastases and Hypercalcemia of Malignancy. Clin Rev Bone Miner Metab 2014. [DOI: 10.1007/s12018-014-9160-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Zhang SJ, Hu Y, Cao J, Qian HL, Jiao SC, Liu ZF, Tao HT, Han L. Analysis on survival and prognostic factors for cancer patients with malignancy-associated hypercalcemia. Asian Pac J Cancer Prev 2014; 14:6715-9. [PMID: 24377594 DOI: 10.7314/apjcp.2013.14.11.6715] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE To explore the incidence, clinical characteristics, diagnosis and treatment strategies, prognosis of patients with malignancy-associated hypercalcemia (MAH). METHODS The data of 115 patients with MAH who were treated at the Medical Oncology Department of Chinese PLA General Hospital from Jan., 2001 to Dec., 2010 was retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier method and the Cox proportional hazard model with statistic software SPSS 18.0. RESULTS The patients had blood calcium levels ranging from 2.77 to 4.87 mmol/L. Except for 9 cases who died or were discharged within 5 days after admission, all other patients recovered to normal blood calcium level after treatment with bisphosphonates or intravenous hydration and diuretics; their survival after occurrence of MAH was from 1 day to 4,051 days, and the median survival time was only 50 days. In the log-rank test, the male, renal metastasis, central nervous system symptoms and hypercalcemia occurring over 140 days after cancer diagnosis were predictors of poor survival (P=0.002, P=0.046, P=0.000, P=0.009). In the COX analysis, being male, central nervous system symptoms and hypercalcemia lasting over 140 days after cancer diagnosis were independent prognostic factors for survival time (RR=2.131, P=0.027; RR=3.054, P=0.002; RR=2.403, P=0.001). According to these factors, a score system was established to predict the patient prognosis and adjust the treatment. CONCLUSION Cancer patients with MAH have an extremely poor median survival. Some independent factors indicate poor prognosis, including male gender, central nervous system symptoms and hypercalcemia lasting over 140 days after cancer diagnosis. The prognostic score can serve as a reference for MAH prognosis and treatment, worthy of further investigation.
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Affiliation(s)
- Su-Jie Zhang
- Department of Oncology, Chinese PLA General Hospital, Beijing, China E-mail :
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Yasuda H. RANKL, a necessary chance for clinical application to osteoporosis and cancer-related bone diseases. World J Orthop 2013; 4:207-217. [PMID: 24147256 PMCID: PMC3801240 DOI: 10.5312/wjo.v4.i4.207] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2013] [Revised: 05/21/2013] [Accepted: 06/20/2013] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis is a common bone disease characterized by reduced bone and increased risk of fracture. In postmenopausal women, osteoporosis results from bone loss attributable to estrogen deficiency. Osteoclast differentiation and activation is mediated by receptor activator of nuclear factor-κB ligand (RANKL), its receptor receptor activator of nuclear factor-κB (RANK), and a decoy receptor for RANKL, osteoprotegerin (OPG). The OPG/RANKL/RANK system plays a pivotal role in osteoclast biology. Currently, a fully human anti-RANKL monoclonal antibody named denosumab is being clinically used for the treatment of osteoporosis and cancer-related bone disorders. This review describes recent advances in RANKL-related research, a story from bench to bedside. First, the discovery of the key factors, OPG/RANKL/RANK, revealed the molecular mechanism of osteoclastogenesis. Second, we established three animal models: (1) a novel and rapid bone loss model by administration of glutathione-S transferase-RANKL fusion protein to mice; (2) a novel mouse model of hypercalcemia with anorexia by overexpression of soluble RANKL using an adenovirus vector; and (3) a novel mouse model of osteopetrosis by administration of a denosumab-like anti-mouse RANKL neutralizing monoclonal antibody. Lastly, anti-human RANKL monoclonal antibody has been successfully applied to the treatment of osteoporosis and cancer-related bone disorders in many countries. This is a real example of applying basic science to clinical practice.
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Abstract
Paraneoplastic syndromes (PNSs) are neoplasm-associated alterations in bodily structure or function or both that occur distant to the tumor. They are an extremely diverse group of clinical aberrations that are associated with the noninvasive actions of the tumor. In many situations, the PNS parallels the underlying malignancy, and therefore, successful treatment of the tumor leads to disappearance of the PNS. Alternatively, recurrence of the PNS after successful treatment signals recurrence of the tumor, and the return of the PNS often significantly precedes the detectable recurrence of the tumor. This is often the case with paraneoplastic hypercalcemia, often referred to as hypercalcemia of malignancy (HM). The most common cause of hypercalcemia in dogs is cancer. Neoplasia is diagnosed in approximately two-thirds of dogs with hypercalcemia vs. approximately one-third in cats. A variety of tumors have been associated with HM. Lymphoma is the most common cause of HM, and the most common anatomical site for dogs with lymphoma-associated HM is the cranial mediastinum. Other tumors associated with HM in dogs and cats include anal sac apocrine gland adenocarcinoma, thyroid carcinoma, multiple myeloma, bone tumors, thymoma, squamous cell carcinoma, mammary gland carcinoma/adenocarcinoma, melanoma, primary lung tumors, chronic lymphocytic leukemia, renal angiomyxoma, and parathyroid gland tumors. As HM is a potential medical emergency, the primary goal in cases of HM is the elucidation of the underlying cause and thereby instituting the appropriate specific therapy.
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Bech A, Smolders K, Telting D, de Boer H. Cinacalcet for hypercalcemia caused by pulmonary squamous cell carcinoma producing parathyroid hormone-related Peptide. Case Rep Oncol 2012; 5:1-8. [PMID: 22379470 PMCID: PMC3290037 DOI: 10.1159/000335676] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Background Current treatments for hypercalcemia caused by lung cell carcinomas producing parathyroid hormone-related peptide (PTH-rp) have limited efficacy, probably because of their lack of effect on PTH-rp secretion. In this case study we explored the efficacy of the calcimimetic cinacalcet as suppressor of PTH-rp production. Patient A 57-year-old male with severe and recurrent hypercalcemia induced by a PTH-rp-producing squamous cell lung carcinoma, stage cT4N3M1b, poorly responding to standard treatments. Results Serum PTH-rp levels were not affected by saline, calcitonin or zoledronate. PTH-rp decreased during chemotherapy and cinacalcet monotherapy. The combination of chemotherapy plus cinacalcet was most effective in rapidly reducing serum calcium and PTH-rp. Conclusion This case study is the first to suggest that cinacalcet may be of value in some cases of PTH-rp-dependent hypercalcemia. Corroborative evidence is needed.
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Affiliation(s)
- Anneke Bech
- Department of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands
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Enomoto T, Furuya Y, Tomimori Y, Mori K, Miyazaki JI, Yasuda H. Establishment of a new murine model of hypercalcemia with anorexia by overexpression of soluble receptor activator of NF-κB ligand using an adenovirus vector. J Bone Miner Metab 2011; 29:414-21. [PMID: 21063739 DOI: 10.1007/s00774-010-0235-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2010] [Accepted: 09/21/2010] [Indexed: 12/15/2022]
Abstract
Hypercalcemia is a significant complication of certain human malignancies that is primarily caused by the release of calcium from bone due to marked bone resorption by osteoclast activation. Osteoclast differentiation and activation is mediated by receptor activator of NF-κB ligand (RANKL). Transgenic mice overexpressing murine soluble RANKL (sRANKL) that we generated previously exhibited severe osteoporosis accompanied with enhanced osteoclastogenesis, but never exhibited hypercalcemia. To analyze the relationship between serum concentration of sRANKL and hypercalcemia and generate a simple and quick hypercalcemia model, an adenovirus vector harboring murine sRANKL cDNA (Ad-sRANKL) was injected i.p. into male C57BL/6 mice. Sera were collected to measure the levels of sRANKL, calcium and biochemical markers of bone turnover. Food intake and body weight were measured every 3 or 4 days. All the mice were killed 2 weeks after the injection, and femurs were collected to measure bone structure and bone mineral density (BMD). Serum sRANKL and calcium increased, peaking on day 7. Food intake and body weight significantly declined on day 7. These results indicated that the mice had anorexia as a symptom of hypercalcemia. Increases in bone resorption and formation markers with a marked decrease in BMD were observed on day 14. These results reflect accelerated bone formation following activation of osteoclasts, indicating coupling between bone formation and resorption. In conclusion, a new murine model of hypercalcemia with anorexia was established by overexpressing sRANKL. This model would be useful for studies of hypercalcemia and coupling between bone formation and resorption.
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Affiliation(s)
- Tetsuro Enomoto
- Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd, 50 Kano-cho, Nagahama, Shiga 526-0804, Japan
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Johnson RW, Nguyen MP, Padalecki SS, Grubbs BG, Merkel AR, Oyajobi BO, Matrisian LM, Mundy GR, Sterling JA. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res 2011; 71:822-31. [PMID: 21189326 PMCID: PMC3077118 DOI: 10.1158/0008-5472.can-10-2993] [Citation(s) in RCA: 160] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Breast cancer frequently metastasizes to bone, in which tumor cells receive signals from the bone marrow microenvironment. One relevant factor is TGF-β, which upregulates expression of the Hedgehog (Hh) signaling molecule, Gli2, which in turn increases secretion of important osteolytic factors such as parathyroid hormone-related protein (PTHrP). PTHrP inhibition can prevent tumor-induced bone destruction, whereas Gli2 overexpression in tumor cells can promote osteolysis. In this study, we tested the hypothesis that Hh inhibition in bone metastatic breast cancer would decrease PTHrP expression and therefore osteolytic bone destruction. However, when mice engrafted with human MDA-MB-231 breast cancer cells were treated with the Hh receptor antagonist cyclopamine, we observed no effect on tumor burden or bone destruction. In vitro analyses revealed that osteolytic tumor cells lack expression of the Hh receptor, Smoothened, suggesting an Hh-independent mechanism of Gli2 regulation. Blocking Gli signaling in metastatic breast cancer cells with a Gli2-repressor gene (Gli2-rep) reduced endogenous and TGF-β-stimulated PTHrP mRNA expression, but did not alter tumor cell proliferation. Furthermore, mice inoculated with Gli2-Rep-expressing cells exhibited a decrease in osteolysis, suggesting that Gli2 inhibition may block TGF-β propagation of a vicious osteolytic cycle in this MDA-MB-231 model of bone metastasis. Accordingly, in the absence of TGF-β signaling, Gli2 expression was downregulated in cells, whereas enforced overexpression of Gli2 restored PTHrP activity. Taken together, our findings suggest that Gli2 is required for TGF-β to stimulate PTHrP expression and that blocking Hh-independent Gli2 activity will inhibit tumor-induced bone destruction.
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Affiliation(s)
- Rachelle W. Johnson
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, Tennessee, United States
| | - Mai P. Nguyen
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States
| | - Susan S. Padalecki
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States
- Department of Urology, University of Texas Health Science Center at San Antonio, Texas, United States
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas, United States
| | - Barry G. Grubbs
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States
| | - Alyssa R. Merkel
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, Tennessee, United States
| | - Babatunde O. Oyajobi
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States
- Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas, United States
| | - Lynn M. Matrisian
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States
| | - Gregory R. Mundy
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, Tennessee, United States
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States
- Department of Veterans Affairs: Tennessee Valley Healthcare System (VISN 9), Nashville, Tennessee, United States
| | - Julie A. Sterling
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States
- Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, Tennessee, United States
- Department of Veterans Affairs: Tennessee Valley Healthcare System (VISN 9), Nashville, Tennessee, United States
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20
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Parathyroid hormone related protein (PTHrP) in tumor progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 720:145-60. [PMID: 21901625 DOI: 10.1007/978-1-4614-0254-1_12] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Parathyroid hormone-related protein (PTHrP) is widely expressed in fetal and adult tissues and is a key regulator for cellular calcium transport and smooth muscle cell contractility, as well as a crucial control factor in cell proliferation, development and differentiation. PTHrP stimulates or inhibits apoptosis in an autocrine/paracrine and intracrine fashion, and is particularly important for hair follicle and bone development, mammary epithelial development and tooth eruption. PTHrP's dysregulated expression has traditionally been associated with oncogenic pathologies as the major causative agent of malignancy-associated hypercalcemia, but recent evidence revealed a driving role in skeletal metastasis progression. Here, we demonstrate that PTHrP is also closely involved in breast cancer initiation, growth and metastasis through mechanisms separate from its bone turnover action, and we suggest that PTHrP as a facilitator of oncogenes would be a novel target for therapeutic purposes.
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21
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Cancer: evolutionary, genetic and epigenetic aspects. Clin Epigenetics 2010; 1:85-100. [PMID: 22704202 PMCID: PMC3365664 DOI: 10.1007/s13148-010-0010-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Accepted: 08/31/2010] [Indexed: 12/22/2022] Open
Abstract
There exist two paradigms about the nature of cancer. According to the generally accepted one, cancer is a by-product of design limitations of a multi-cellular organism (Greaves, Nat Rev Cancer 7:213–221, 2007). The essence of the second resides in the question “Does cancer kill the individual and save the species?” (Sommer, Hum Mutat 3:166–169, 1994). Recent data on genetic and epigenetic mechanisms of cell transformation summarized in this review support the latter point of view, namely that carcinogenesis is an evolutionary conserved phenomenon—a programmed death of an organism. It is assumed that cancer possesses an important function of altruistic nature: as a mediator of negative selection, it serves to preserve integrity of species gene pool and to mediate its evolutionary adjustment. Cancer fulfills its task due apparently to specific killer function, understanding mechanism of which may suggest new therapeutic strategy.
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22
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Asakawa A, Fujimiya M, Niijima A, Fujino K, Kodama N, Sato Y, Kato I, Nanba H, Laviano A, Meguid MM, Inui A. Parathyroid hormone-related protein has an anorexigenic activity via activation of hypothalamic urocortins 2 and 3. Psychoneuroendocrinology 2010; 35:1178-86. [PMID: 20188481 DOI: 10.1016/j.psyneuen.2010.02.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2009] [Revised: 01/18/2010] [Accepted: 02/02/2010] [Indexed: 10/19/2022]
Abstract
Cancer cachexia is reported to be a major cause of cancer-related death. Since the pathogenesis is not entirely understood, only few effective therapies have been established. Since myriad tumors produce parathyroid hormone-related protein (PTHrP), plasma concentrations of PTHrP are increased in cancer cachexia. We measured the food intake, gastric emptying, conditioned taste aversion (CTA), and gene expression of hypothalamic neuropeptides in mice after administering PTHrP intraperitoneally. We administered PTHrP intravenously in rats and examined the gastroduodenal motility and vagal nerve activities. We also examined whether chronic administration of PTHrP influenced the food intake and body weight. Peripherally administered PTHrP induced negative energy balance by decreasing the food intake and gastric emptying; however, it did not induce CTA. The mechanism involved the activation of hypothalamic urocortins 2 and 3 through vagal afferent pathways and the suppression of gastroduodenal motor activity. The continuous infusion of PTHrP reduced the food intake and body weight gain with a concomitant decrease in the fat and skeletal muscle. Our findings suggest that PTHrP influences the food intake and body weight; therefore, PTHrP can be considered as a therapeutic target for cancer cachexia.
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Affiliation(s)
- Akihiro Asakawa
- Department of Social and Behavioral Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
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23
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Sargent JTS, Smith OP. Haematological emergencies managing hypercalcaemia in adults and children with haematological disorders. Br J Haematol 2010; 149:465-77. [PMID: 20377591 DOI: 10.1111/j.1365-2141.2010.08173.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hypercalcaemia is a common metabolic complication of malignant disease often requiring emergency intervention. Although it is more frequently associated with solid tumours, malignancy-associated hypercalcaemia (MAH) is seen in a significant number of patients with blood diseases. Its association with myeloma and adult T-cell leukaemia/lymphoma is well recognized but the incidence of hypercalcaemia in other haematological neoplasms, affecting adults and children, is less clearly defined. Haematologists need to be familiar with the clinical manifestations of, the differential diagnosis to be considered and the most effective management strategies that are currently available for MAH. The key components of management of MAH include aggressive rehydration, specific therapy to inhibit bone resorption and, crucially, treatment of the underlying malignancy. Bisphosphonates have revolutionized the management of MAH over the last 20 years, however the elucidation of molecular pathways implicated in MAH is facilitating the development of more targeted approaches to treatment.
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Affiliation(s)
- Jeremy T S Sargent
- Trinity College, and Department of Haematology & Oncology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
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24
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25
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Central mechanisms controlling appetite and food intake in a cancer setting: an update. Curr Opin Support Palliat Care 2008; 1:306-11. [PMID: 18685380 DOI: 10.1097/spc.0b013e3282f14c4e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
PURPOSE OF REVIEW Cachexia, also known as disease-associated wasting, is an important factor in the mortality of many patients with diseases such as cancer, as well as renal and congestive heart failure. Yet the syndrome is not yet well defined, making diagnosis difficult and often subjective on the part of the physician. Nor are the central mechanisms of cachexia fully elucidated. Recent studies have begun to address these gaps by focusing on three areas: the role of cytokines in cachexia, other proteins and peptides that might be involved, and potential treatments for this devastating syndrome. RECENT FINDINGS Cachexia can be caused, in the absence of disease, by inflammatory stimuli and some chemotherapy drugs, suggesting possible central mechanisms in cachexia. Promising treatments include melanocortin antagonism and some hormones. SUMMARY While more research is necessary to illuminate causal mechanisms and uncover potential therapies of cachexia, several of its major molecular pathways have become elucidated, suggesting directions for therapeutic approaches.
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26
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Mixed hepato/cholangiocarcinoma with paraneoplastic hypercalcemia. ACTA ACUST UNITED AC 2008; 15:224-7. [DOI: 10.1007/s00534-007-1235-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Accepted: 05/07/2007] [Indexed: 01/17/2023]
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27
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28
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McDonald IM, Austin C, Buck IM, Dunstone DJ, Gaffen J, Griffin E, Harper EA, Hull RAD, Kalindjian SB, Linney ID, Low CMR, Patel D, Pether MJ, Raynor M, Roberts SP, Shaxted ME, Spencer J, Steel KIM, Sykes DA, Wright PT, Xun W. Discovery and characterization of novel, potent, non-peptide parathyroid hormone-1 receptor antagonists. J Med Chem 2007; 50:4789-92. [PMID: 17850061 DOI: 10.1021/jm0707626] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.
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Affiliation(s)
- Iain M McDonald
- James Black Foundation, 68 Half Moon Lane, Dulwich, London, SE24 9JE, UK.
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29
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Lorch G, Gilmore JL, Koltz PF, Gonterman RM, Laughner R, Lewis DA, Konger RL, Nadella KS, Toribio RE, Rosol TJ, Foley J. Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice. Br J Cancer 2007; 97:183-93. [PMID: 17533397 PMCID: PMC2360295 DOI: 10.1038/sj.bjc.6603828] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
The purpose of this study was to evaluate the role of the epidermal growth factor receptor (EGFR) in parathyroid hormone-related protein (PTHrP) expression and humoral hypercalcaemia of malignancy (HHM), using two different human squamous-cell carcinoma (SCC) xenograft models. A randomised controlled study in which nude mice with RWGT2 and HARA xenografts received either placebo or gefitinib 200 mg kg−1 for 3 days after developing HHM. Effectiveness of therapy was evaluated by measuring plasma calcium and PTHrP, urine cyclic AMP/creatinine ratios, and tumour volumes. The study end point was at 78 h. The lung SCC lines, RWGT2 and HARA, expressed high levels of PTHrP mRNA as well as abundant EGFR protein, but very little erbB2 or erbB3. Both lines expressed high transcript levels for the EGFR ligand, amphiregulin (AREG), as well as, substantially lower levels of transforming growth factor-α (TGF-α), and heparin binding-epidermal growth factor (HB-EGF) mRNA. Parathyroid hormone-related protein gene expression in both lines was reduced 40–80% after treatment with 1 μM of EGFR tyrosine kinase inhibitor PD153035 and precipitating antibodies to AREG. Gefitinib treatment of hypercalcaemic mice with RWGT2 and HARA xenografts resulted in a significant reduction of plasma total calcium concentrations by 78 h. Autocrine AREG stimulated the EGFR and increased PTHrP gene expression in the RWGT2 and HARA lung SCC lines. Inhibition of the EGFR pathway in two human SCC models of HHM by an anilinoquinazoline demonstrated that the EGFR tyrosine kinase is a potential target for antihypercalcaemic therapy.
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MESH Headings
- Amphiregulin
- Animals
- Antineoplastic Agents/therapeutic use
- Carcinoma, Squamous Cell/complications
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Line, Tumor
- EGF Family of Proteins
- ErbB Receptors/analysis
- ErbB Receptors/antagonists & inhibitors
- ErbB Receptors/metabolism
- Gefitinib
- Gene Expression Regulation, Neoplastic
- Glycoproteins/analysis
- Glycoproteins/metabolism
- Humans
- Hypercalcemia/drug therapy
- Hypercalcemia/etiology
- Hypercalcemia/genetics
- Intercellular Signaling Peptides and Proteins/analysis
- Intercellular Signaling Peptides and Proteins/metabolism
- Lung Neoplasms/complications
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Mice
- Mice, Nude
- Mitogen-Activated Protein Kinase Kinases/metabolism
- Parathyroid Hormone-Related Protein/genetics
- Quinazolines/therapeutic use
- RNA, Messenger/analysis
- RNA, Messenger/metabolism
- Receptor, ErbB-2/analysis
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/metabolism
- Receptor, ErbB-3/analysis
- Receptor, ErbB-3/genetics
- Receptor, ErbB-3/metabolism
- Signal Transduction
- Xenograft Model Antitumor Assays
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Affiliation(s)
- G Lorch
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
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30
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Liao J, McCauley LK. Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP). Cancer Metastasis Rev 2007; 25:559-71. [PMID: 17165129 DOI: 10.1007/s10555-006-9033-z] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Parathyroid hormone related protein (PTHrP) is a well characterized tumor derived product that also has integral functions in normal development and homeostasis. PTHrP is produced by virtually all tumor types that metastasize to bone and numerous studies have demonstrated a correlation between PTHrP expression and skeletal localization of tumors. PTHrP has prominent effects in bone via its interaction with the PTH-1 receptor on osteoblastic cells. Through indirect means, PTHrP supports osteoclastogenesis by upregulating the receptor activator of NFkappaB ligand (RANKL) in osteoblasts. PTHrP also regulates osteoblast proliferation and differentiation in manners that are temporal and dose dependent. Bone turnover has been implicated in the localization of tumors to bone and PTHrP increases bone turnover. Bone turnover results in the release of growth factors such as TGFbeta and minerals such as calcium, both of which impact tumor cell growth and contribute to continued PTHrP production. PTHrP also has anabolic properties and could be in part responsible for osteoblastic type reactions in prostate cancer. Finally, emerging roles of PTH and PTHrP in the support of hematopoietic stem cell development in the bone marrow microenvironment suggest that an interaction between hematopoietic cells and tumor cells warrants further investigation.
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Affiliation(s)
- Jinhui Liao
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA.
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31
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Farias MLFD. [Hypercalcemia of malignancy: clinical features, diagnosis and treatment]. ARQUIVOS BRASILEIROS DE ENDOCRINOLOGIA E METABOLOGIA 2006; 49:816-24. [PMID: 16444366 DOI: 10.1590/s0004-27302005000500024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hypercalcemia associated with malignancies is reported in up to 20 to 30% of patients with cancer during the course of the disease, and points to a poor prognosis. Symptoms related to the central nervous system, as progressive mental impairment, stupor and coma, predominate. Alterations in kidney function (water-concentrating defect leading to polyuria) and gastrointestinal tract (anorexia, nausea, vomiting) corroborate to dehydration and a further increase in serum calcium. Cancer-induced hypercalcemia may be classified as: 1) local osteolytic hypercalcemia (LOH), due to marked increase in osteoclastic bone resorption in areas surrounding the malignant cells within the marrow space; 2) humoral hypercalcemia of malignancy, caused by the secretion of parathyroid hormone-related protein (PTHrP) by the malignant tumor; 3) ectopic hyperparathyroidism; 4) 1,25(OH)2 D-secreting tumors. Adequate control of hypercalcemia is necessary to give the patient time to respond to anti-cancer therapy. Volume expansion with saline will correct dehydration, improve glomerular filtration and increase urinary calcium excretion, which may be further stimulated by loop diuretics. Intravenous bisphosphonates are the most effective agents to control hypercalcemia, as they block osteoclastic osteolysis and also have antitumoral effects, decreasing bone metastases. New approaches to control the skeletal manifestations of malignancies are anti-PTHrP and anti-RANKL antibodies, osteoprotegerin, and also proteasome inhibitors in the case of multiple myeloma.
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Abstract
The hypothesis introduces the idea that there is a critical level of mutagenesis that triggers a program of organism death by means of proliferation of killer cells. Similarly to apoptosis, which is an altruistic suicidal act of a faulty cell threatening the stability of a multicellular organism, a malignant tumor is an altruistic suicide of an individual carrier of harmful alleles threatening genetic stability of the population.
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Affiliation(s)
- A V Lichtenstein
- Institute of Carcinogenesis, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia.
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33
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DeMauro S, Wysolmerski J. Hypercalcemia in breast cancer: an echo of bone mobilization during lactation? J Mammary Gland Biol Neoplasia 2005; 10:157-67. [PMID: 16025222 DOI: 10.1007/s10911-005-5398-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Hypercalcemia is a frequent complication of breast cancer which causes significant morbidity and mortality. Most commonly, it occurs in patients with multiple skeletal metastases. However, in a significant minority of patients, calcium levels become elevated in the absence of skeletal disease. In both instances, hypercalcemia is the result of pathological bone resorption caused by the secretion of cytokines that stimulate osteoclast differentiation and activity. One of these cytokines is parathyroid hormone-related protein (PTHrP). PTHrP is also secreted by normal breast cells during lactation to increase bone resorption and liberate skeletal calcium stores for the purposes of milk production. Therefore, the pathophysiology of hypercalcemia in breast cancer patients mimics the physiological processes that normally regulate calcium metabolism during lactation. Current therapy for hypercalcemia in breast cancer patients relies on the inhibition of bone resorption by a class of drugs known as bisphophonates. Newer therapies in development target cytokines involved in the recruitment and activation of osteoclasts by tumor cells.
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Affiliation(s)
- Samantha DeMauro
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
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34
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Affiliation(s)
- Andrew F Stewart
- Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh 15213, USA.
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35
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Bazar KA, Yun AJ, Lee PY. “Starve a fever and feed a cold”: feeding and anorexia may be adaptive behavioral modulators of autonomic and T helper balance. Med Hypotheses 2005; 64:1080-4. [PMID: 15823688 DOI: 10.1016/j.mehy.2004.05.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2004] [Accepted: 05/04/2004] [Indexed: 11/21/2022]
Abstract
Anorexia is a common symptom accompanying infections, but the teleology of the phenomenon remains unexplained. We hypothesize that anorexia may represent a prehistoric behavioral adaptation to fight infection by maintaining T helper (Th)2 bias, which is particularly vital in fighting bacterial pathogens. Specifically, we propose that anorexia may avert the reduction of Th2/Th1 ratio by preventing feeding-induced neurohormonal and vagal output from the gut. Emerging evidence suggests that the vagal and neurohormonal output of the gut during feeding promotes Th1 function, which is desirable in fighting viral infections. Since fever may be an adaptation to fight bacteria and "colds" are generally viral in origin, the adage "starve a fever and feed a cold" may reflect a sensible behavioral strategy to tilt autonomic and Th balance in directions that are optimal for fighting the particular type of infection. The ability to modulate T helper balance through the neurohormonal and autonomic axis by adjusting food intake may be the mechanism behind other unexplained clinical observations such as the improved outcomes of ICU patients after enteric versus parenteric feedings. Compared to the prehistoric period when bacterial infection was commonplace, the anorexic response may be less adaptive today when viruses and cancers have become common triggers of anorexia. By promoting host anorexia, cachexia, and insomnia, cancers and viruses can deter behaviors such as digestion and sleep that would raise vagal and Th1 activity against tumors and viruses. Hydration and sleep, unexplained but widely accepted recommendations for flu patients, may also work by promoting vagal and Th1 functions. Modulating feeding, hydration, and sleep may prove beneficial in treating other conditions associated with abnormal autonomic and Th balance.
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Affiliation(s)
- Kimberly A Bazar
- Department of Dermatology, San Mateo Medical Center, 222 West, 39th Avenue, San Mateo, CA 94403, USA.
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36
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Abstract
Autonomic balance, a function generally under host control, is subject to modulation by other signalers. In some cases, modulation of host autonomic function through behavioral and physical stressors exerted by another individual may have negative consequences for the stress recipient by inducing sympathetic bias. Modulation of autonomic function may sometimes benefit one party at the expense of another. Tumors and HIV are examples of illegitimate signalers who may induce host sympathetic bias to promote their own growth and evade host immune surveillance. Paraneoplastic and paraviral syndromes such as hypertrophic osteoarthopathy, QTc prolongation, insomnia, and cachexia could be viewed as epiphenomena related to the tumoral and viral manipulation of host autonomic balance. In a more general framework, other paraneoplastic and paraviral syndromes may represent epiphenomena related to modulation of endocrine, cytokine, and autonomic functions by tumors and viruses to promote their own survival. Spatial distribution of cancers and viruses within the host may reflect affinity for strategic locations that facilitate manipulation of a variety of host functions including autonomic, endocrine, and cytokine regulation. A more general for understanding spatial distribution of diseases based on gradients of autonomic balance in the body are explored. Darwinian perspectives are discussed.
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Affiliation(s)
- A Joon Yun
- Department of Radiology, Stanford University, 470 University Avenue, Palo Alto, CA 94301, USA.
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