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More than 10 million people are diagnosed with cancer every year and by 2020 it is estimated that 15 million new cases will be diagnosed each year. In 2005 cancer caused 7.6 million deaths world-wide. In the United States, it is estimated that cancer has now eclipsed heart disease as the leading cause of death as 1 in 4 US deaths are cancer related.
Despite the increasing prevalence of cancer, improvements in the detection and treatment of most types of cancers have resulted in significantly increased survival rates. For many patients, pain is the first sign of cancer and the majority of individuals will experience moderate to severe pain during the course of their disease and into survivorship. Interestingly, several therapies that are given to control pain also appear to have significant effects on tumor growth and metastasis and thus may not only relieve pain but increase survival of cancer patients.
The major efforts of the lab is to understand why cancer cells preferentially metastasize to specific organs such as bone, what role nerves that innervate the bone play in tumor metastasis to bone, and to develop a mechanism based understanding and therapies to prevent the metastasis or tumors to bone, the growth of tumor in bone and reduce the severe pain that tumor metastases can cause. Findings from these studies may provide mechanistic insight and allow the development of new therapies which may improve the quality of life and survival of cancer patients.
Stem Cells, Pain, and the Injured and Aged Skeleton
Although skeletal pain is the most common reason individuals seek medical attention, it is remarkable how little we know about the specific mechanisms that drive skeletal pain. While bone is frequently thought of as a rather static organ, in fact it is remarkably malleable and one of the most dynamic organs of the body in that stem cells that reside in bone are constantly remodeling the bone and pivotal cells involved in the bones response to general use, loading of the bone, injury, and aging.
Currently, there is a significant unmet clinical need to develop new therapies that relieve skeletal pain due to fracture, osteoarthritis, orthopeadic procedures, etc, that both relieve the pain and stimulate stem cells in the bone to proliferate, form appropriate bone remodeling cells and produce new, high quality and bone and joint tissue following injury or aging, These projects involve working at the interface between neurobiology, bone biology and stem cells biology and have the potential to halt or reverse changes that occur in the human skeleton as a result of aging, injury or genetic disorders.
(Publications selected from 178 peer-reviewed publications)
Mantyh PW, Pinnock RD, Downes CP, Goedert M, and Hunt SP. (1984) Correlation between inositolphospholipid hydrolysis and substance P receptors in rat CNS. Nature 309(5971):795-7.
Mantyh PW, Johnson DJ, Boehmer CG, Catton MD, Vinters HV, Maggio JE, Too HP, and Vigna SR. (1989) Substance P receptor binding sites are expressed by glia in vivo after neuronal injury. Proceedings of the National Academy of Sciences of the United States of America 86(13):5193-7.
Mantyh PW, DeMaster E, Malhotra A, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI,
Vigna SR, Maggio JE, and Simone DA. (1995) Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268(5217):1629-32.
Lui H, Mantyh PW, and Basbaum AI. (1997) NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386(6626):721-4.
Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters RS, Lappi DA, Wiley RG, and Simone DA. (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278(5336):275-9.
Schwei MJ, Honore P, Rogers SD, Salak-Johnson JL, Finke MP, Ramnaraine ML, Clohisy DR,
and Mantyh PW. (1999) Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. Journal of Neuroscience 19(24):10886-97.
Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, Finke MP, Li J, Lappi DA, Simone DA, and Mantyh PW. (1999) Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 286(5444):1558-61.
Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB, O'Keefe PF, Ramnaraine ML, Clohisy DR, and Mantyh PW. (2000) Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nature Medicine 6(5):521-8.
Halvorson KG, Kubota K, Sevcik MA, Lindsay TH, Sotillo JE, Ghilardi JR, Rosol TJ, Shelton DL and Mantyh PW. (2005) A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone. Cancer Research 65(20):9426-9435.
Lindsay TH, Jonas BM, Sevcik MA, Kubota K, Halvorson KG, Ghilardi JR, Kuskowski MA, Stelow MD, Mukherjee P, Gendler S, Wong GY and Mantyh PW. (2005) Pancreatic cancer pain and its correlation with changes in tumor vasulature, macrophage infiltration, neuronal innervation, body weight and disease Progression. Pain 119(1-3):233-46.
Sevcik MA, Jonas BM, Lindsay TH, Halvorson KG, Ghilardi JR, Kuskowski MA, Mukherjee P, Maggio JE, Mantyh PW. (2006) Endogenous opioids inhibit early stage pancreatic pain in a mouse model of pancreatic cancer. Gastroenterology 131:900-910.
Peters CP, Jimenez-Andrade JM, Jonas BM, Sevcik MA, Koewler NJ, Ghilardi JR, Wong GY, and Mantyh PW. (2006) Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Experimental Neurology 203(1):42-54.
Mantyh PW. (2006) Cancer pain and its impact on diagnosis, survival and quality of life. Nature Reviews Neuroscience (10):797-809.
Jimenez-Andrade JM, Martin CD, Koewler NJ, Freeman KT, Sullivan LJ, Halvorson KG,Barthold
CM, Peters CM,Buss RJ, Mantyh PW. (2007) Nerve growth factor Sequestering therapy attenuates skeletal pain following fracture. Pain. 133(1-3):183-96
Freeman KT, Koewler NJ, Jimenez-Andrade JM, Buus RJ, Herrera MB, Martin CD, Ghilardi JR, Kuskowski MA, Mantyh PW. (2008) A fracture pain model in the rat: adaptation of a closed femur fracture model to study skeletal pain. Anesthesiology. 108(3):473-83.