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Novel regulatory mechanisms for lung cancer growth

Institution: Veterans Medical Research Foundation
Investigator(s): Randolph Hastings, M.D., Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0161H Award: $620,032
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Parathyroid hormone-related protein (PTHrP) is a protein that was discovered in the blood of a patient with lung cancer. PTHrP is responsible for causing high levels of calcium in the blood of such patients and patients with other types of cancer. PTHrP is made by the lung cancer cells and has been detected in cells from all of the types of lung cancer. Many investigators have studied the role of PTHrP in causing elevated blood calcium levels in cancer patients, but PTHrP may also have other effects. For example, PTHrP stimulates many lung cancer cells to grow and proliferate. Thus, PTHrP produced by the cells might stimulate the growth of lung tumors or spread of the cancer to other parts of the body. This project fits with the research priorities of the TRDRP because it will study the processes important in growth of lung cancer, a disease caused by tobacco use or exposure, and might lead to development of new treatments for lung cancer. The first aim is to learn whether PTHrP stimulates proliferation of lung cancer cells by being released from the cells and acting at sites on the cell surface, or by being transported inside the cell to the nucleus, the site containing the cell’s DNA. This knowledge is important for understanding the cancer disease process and will be significant for designing therapies related to PTHrP. The experiments will involve genetically modifying lung cancer cells to make PTHrP that is released from the cell or PTHrP that is transported to the nucleus. The different cells will be grown in plates and the rate of cell proliferation will be measured and compared. The second aim is to learn whether PTHrP stimulates lung tumors to grow in the same way it stimulates the cancer cells in culture plates to grow. Tumors will be formed by implanting the cells into the lungs of mice that have compromised immune systems and cannot reject the foreign cells. The cells will be modified as described above to make PTHrP that is either released from the cells or transported to the nucleus. The cells will also be modified to be fluorescent. After six weeks, lung tumor growth will be evaluated by inspecting the lungs, measuring the fluorescence, or examining the lungs microscopically. The third aim is to determine if lung tumor growth can be slowed by treatments that reduce the effects of PTHrP on lung cancer cells. Lung tumors will be formed in mice, as in the second aim, and mice will be treated with antibodies against PTHrP, drugs that counter the effects of PTHrP, or substances that prevent the cells from making PTHrP. Lung tumor growth will be measured as described for the second aim. The results of these studies will improve our understanding of how lung cancer grows, and may lead to new therapies for lung cancer.
Publications

Parathyroid hormone-related protein regulates the growth of orthotopic human lung tumors in athymic mice.
Periodical: Cancer Index Medicus:
Authors: Hastings RH, Burton DW, Quintana RA, Biederman E, Guijral A, and Deftos LJ ART
Yr: 2001 Vol: 92 Nbr: 6 Abs: Pg: 1402-1410

Identification of a nuclear localization sequence in the human-specific, carboxy-terminal region of PTHrP.
Periodical: Journal of Bone & Mineral Research Program and Abstracts Index Medicus:
Authors: Hastings RH, Wu JY, Burton DW, and Deftos LJ ABS
Yr: 2001 Vol: S548 Nbr: Abs: Pg: 1-173

thyroid hormone-related protein response to hyperoxic lung injury.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Hastings RH, Ryan RM, D'Angio CT, Holm BA, Patel A, Quintana R, Biederman E, et al. ART
Yr: 2002 Vol: 282 Nbr: Abs: Pg: L1198-L1208

Parathyroid hormone-related protein 38-64 regulates lung cell proliferation after silica injury.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Hastings RH, Asirvatham A, Quintana R, Sandoval R, Dutta R, Burton DW, Deftos LJ ART
Yr: 2002 Vol: 283 Nbr: Abs: Pg: L12-L21

Role of parathyroid hormone-related protein in lung cancer cell survival.
Periodical: Chest Index Medicus:
Authors: Hastings RH, Araiza F, Burton DW, Deftos LJ ART
Yr: 2004 Vol: 125 Nbr: Abs: Pg: 150S

Amino-terminal PTHrP peptides in lung cancer cell lines identified by mass spectrometry.
Periodical: Journal of Bone & Mineral Research Program and Abstracts Index Medicus:
Authors: Miller R, Schilling B, Burton DW, Gibson B, Hastings RH, Deftos LJ, Hook VH ABS
Yr: 2002 Vol: 17 Nbr: Abs: Pg: S286

Amino-terminal and mid-molecule PTHrP stimulate phosphatidylcholine in silica-lung injury.
Periodical: Journal of Bone & Mineral Research Program and Abstracts Index Medicus:
Authors: Hastings RH, Quintana RA, Sandoval R, Rascon Y, Burton DW, Deftos LJ ABS
Yr: 2002 Vol: 17 Nbr: S491 Abs: Pg:

Pro-apoptotic effects of parathyroid hormon-related protein in type II pneumocytes.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Hastings RH ART
Yr: 0 Vol: Nbr: Abs: Pg:

Mechanisms of in vivo alveolar protein clearance.
Periodical: American Journal of Physiology Index Medicus:
Authors: Hastings RH, Folkesson HG, Matthay MA ART
Yr: 0 Vol: Nbr: Abs: Pg:

Parathyroid hormone-related protein regulates lung phospholipids through effects on type II cell proliferation in silica lung injury.
Periodical: FASEB Journal Index Medicus:
Authors: Hastings RH, Quintana R, Rascon Y, Duey D, Burton DW, Deftos LJ ABS
Yr: 2003 Vol: 17 Nbr: 5 Abs: Pg: A830

Parathyroid hormone-related protein sensitizeds alveolar type II cells to apoptosis.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Hastings RH, Quintana R, Sandoval R, Rascon Y, Duey D, Burton DW, Deftos LJ ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Proteolysis of ProPTHrP(1-141) by prohormone thiol protease (PTP) at multibasic residues generates PTHrP-related peptides: Implications for PTHrP peptide production in lung cancer cells.
Periodical: Biochemistry and Biophysics Research Communications Index Medicus:
Authors: Hook VYH, Burton DW, Yasothornsrikul S, Hastings RH, Deftos IJ ART
Yr: 2001 Vol: 285 Nbr: Abs: Pg: 932-938

Comparative tissue distribution of the processing enzymes prohormone thoil protease, and prohormone convertases 1 and 2, in human PTHrP-producing cell lines and mammalian neuroendocrine tissues.
Periodical: Endocrine Index Medicus:
Authors: Deftos IJ, Burton DW, Hastings RH, Terkeltaub R, Hook VYH ART
Yr: 2001 Vol: 15 Nbr: 2 Abs: Pg: 217-224

Parathyroid hormone-related protein ameliorates death receptormediated apoptosis in lung cancer cells.
Periodical: American journal of physiology. Cell physiology Index Medicus:
Authors: Hastings RH, Araiza F, Burton DW, Zhang L, Bedley M, Deftos IJ ART
Yr: 2003 Vol: 285 Nbr: 6 Abs: Pg: C1429-1436

Parathyroid hormone-related protein regulates apoptosis in lung cancer cells through protein kinase A.
Periodical: American journal of physiology. Cell physiology Index Medicus:
Authors: Hastings RH, Araiza F. Burton DW, Bedley M, Deftos IJ ART
Yr: 2004 Vol: 287 Nbr: 6 Abs: Pg: C1616-C1622

Monitoring of skeletal progression of prostate cancer by GFP imaging x-ray, and serum OPG and PTHrP.
Periodical: Prostate Index Medicus:
Authors: Burton DW, Geller J, Yang M, Jiang P, Barken I, Hastings RH, Hoffman RM, et al. ART
Yr: 2004 Vol: Nbr: Abs: Pg:

Parathyroid hormone-related protein and lung biology.
Periodical: Respiratory Physiological Neurobiological Index Medicus:
Authors: Hastings RH ART
Yr: 2004 Vol: 142 Nbr: 2 - 3 Abs: Pg: 95-113

Apoptotic effects of parathyroid hormone related protein in prostate cancer cells.
Periodical: Journal of Bone & Mineral Research Program and Abstracts Index Medicus:
Authors: Matheshwari VV, Burton DW, Hastings RH, Aguilera JA, Pardo FS, Deftos IJ ART
Yr: 2003 Vol: 18 Nbr: Suppl 2 Abs: Pg: S199

Parathyroid hormone-related protein promotes lung cancer cell survival.
Periodical: Journal of Bone & Mineral Research Program and Abstracts Index Medicus:
Authors: Hastings RH, Araiza F, Burton DW, Deftos IJ ART
Yr: 2003 Vol: 18 Nbr: Suppl 2 Abs: Pg: S113

PTHrP mediates apoptosis resistance in lung cancer cells through PKA-dependent pathways.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Hastings R, Araiza F, Bedley M, Burton D, Deftos L ART
Yr: 2004 Vol: 169 Nbr: 7 Abs: Pg: A239