In the United States alone, the American Cancer Society predicts 234,460 new cases of prostate cancer and 214,460 new cases of breast cancer in 2006. Despite our advances in the detection and treatment of these primary cancers, 27,350 men and 40,970 women will succumb to the disease. These deaths are primarily due to metastasis. Interestingly, both prostate and breast cancer have a strong propensity (>80%) to metastasize to the bone and in the bone environment, the metastatic tumor cells manipulate the normal cells of the bone to stimulate bone growth (osteoblasts) and destruction (osteoclasts). Bone metastases cause several complications for the patient including hypercalcemia and intense pain which greatly affect the patient’s quality of life. At the moment, limited therapies exist for the treatment of bone metastases. I am interested in understanding how the metastatic tumor cells communicate osteoblasts and osteoclasts in order to promote extensive changes in the bone. Identifying these factors will be a powerful approach for the development of new therapies that will prevent the progression of metastatic tumors in the bone and ultimately be of great benefit to the patients suffering with this disease. To study the tumor:host interactions, I am using a number of animal models that accurately recapitulate the clinical scenarios of prostate and breast cancer induced osteoblastic and/or osteolytic responses (Figure 1). Using the prostate model, we have previously observed that several members of the matrix metalloproteinase (MMP) family, including MMP-7, are markedly overexpressed at the tumor bone interface. Using animals genetically deficient for MMP-7, we demonstrated that this enzyme significantly contributes to prostate tumor induced osteolysis. Thus the selective inhibition of MMP-7 activity is potentially an exciting approach for preventing prostate tumor progression in the bone. Using the power of micro-array and proteomics, we are currently concentrating on a comprehensive effort to define the proteins involved in tumor bone communication.

Areas Of Interest:

Matrix Metalloproteinases (MMPs), MMP-7, MMP substrates, MMP inhibitors, prostate metastasis to bone, prostate tumor induced osteoblastic response, prostate tumor induced osteolytic response, osteoblast differentiation, osteoclast activation.

Research Skills:

• Animal Surgery/ Drug Treatment/ Animal Care/ Animal Husbandry (5 years experience)
• Mammary gland clearing and injection for the implantation and longitudinal study of breast cancer.
• Ovarectomy/Prostectomy. Necessary surgical technique for the control or contribution of estrogen/progesterone and androgens on tumor formation and growth.
• Intratibial Injection for the delivery of breast cancer cell lines to the bone environment in order to study tumor mediated bone destruction over time.
• Intracardiac Injection to study the metastasis or spread of breast cancer to the skeleton.
• Cranial transplant of prostate tumor tissue to the calvaria of immunocompromised mice. Model accurately recapitulates the human clinical scenario of prostate cancer induced bone growth and destruction.
• Tail vein injection for the delivery of tumor cell lines specifically to the mouse lung or the testing of chemotherapeutic reagents for the treatment of tumor bearing mice.
• Retro-orbital injection for the delivery of chemotherapeutic reagents for the treatment of tumor bearing mice, the delivery of radiolabeled isotopes and substrates for imaging tumors in live animals.
• Implantation of coralline scaffold. I have pioneered the development of an in vivo model of bone formation in the mouse. Coral scaffold is surgically implanted to the femoral artery of mice. The addition of bone forming cytokines induces an influx of bone progenitor cells into the coral and subsequent bone formation.
• Animal care. Vanderbilt University requires that all investigators are registered and trained with the Institutional Animal Care and Use Committee I have several years of training in the surgical pre-operative and post operative care of rodents.
• Breeding. My studies involve the use of mice that are genetically deficient in several proteins of interest. I have several years experience in the breeding of these animals and in the strategies required to generate genetically deficient animals on different mouse backgrounds.
• Use of small animal imaging techniques including the In Vivo Imaging SystemTM from Xenogen for the detection of luciferase expressing cells, micro computer tomography (microCT) scanning to measure tumor induced bone destruction and micro photon emission tomography (microPET) to detect growing tumors
  

Recent Publications:

Morgan M. and Lynch CC. (1998). Isolation and characterization of novel human antibodies to MMP-9 from a phage display library. British Journal of Cancer. 78: 41

McDonnell S, Morgan M. and Lynch CC. (1999). Role of Matrix metalloproteases in normal and disease processes. Biochem. Soc. Trans. 27: 734-739.

Lynch CC and McDonnell S. (2000). The role of matrilysin (MMP-7) in leukaemia invasion and metastasis. Clin Exp Met. 18: 401-6

Harmey JH, Bucana CD, Lu W, Byrne AM, McDonnell S, Lynch CC, Bouchier-Hayes D and Dong Z. (2002).  Lipopolysaccharide induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion.  Int J Cancer. 101: 415-422

Lynch CC and Matrisian LM. (2002).  MMPs in tumor:host communication. Differentiation. 70: 561-73.

Lynch CC, Crawford, HC, Matrisian, LM and McDonnell S. (2004). Epidermal growth factor upregulates matrix metalloproteinase-7 expression through activation of PEA3 transcription factors. Int. J. Oncology. 24: 1565-1573.

Lynch CC, Hikosaka, A, Acuff HB, Martin MD, Kawai, N, Singh, RK, Vargo-Gogola, T, Begtrup, JL, Peterson, TE, Fingleton, B, Shirai, T, Matrisian LM and Futakuchi, M. (2005) Matrix Metalloproteinase-7 [MMP-7] promotes prostate cancer induced osteolysis via the solubilization of receptor activator of nuclear-kB ligand [RANKL]. Cancer Cell. 7: 485-496.

Lynch CC and Matrisian, LM. (2006). MMP-3 solubilized RANKL promotes osteoclast activation. Connective Tissue Res.  (In press).

Halpern J, Lynch CC, Hamming D, Fleming J, Schwartz H, Matrisian LM, and Holt G. (2006). The development of a novel murine bone bioreactor to study the effects of bone metastasis. (Submitted).

Lynch, CC, Vargo-Gogola, T, Martin, MD, Lynggi B, Fingleton, B, Crawford, HC, Carpenter, G, and Matrisian, LM.  (2006) MMP-7 expression induces tumorigenicity of mammary epithelial cells via cleavage of E-cadherin and the ErbB-4 receptor. (Submitted)