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Experimental Studies on Prostate Cancer and Lung Cancer Bone Metastasis

Author: DengXiYun
Tutor: CaoYa
School: Central South University
Course: Pathology and Pathophysiology
Keywords: matrix metalloproteinases tissue inhibitors of metalloproteinases prostate cancer lung cancer bone metastasis adenovims SCID/Hu mouse model parathyroid hormone-related protein ezrin calvarial bone
CLC: R734.2
Type: PhD thesis
Year: 2006
Downloads: 278
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Abstract


Bone metastases represent a major complication of various malignancies including cancers of the breast, prostate and lung, and are responsible for most of the morbidity associated with these cancers. The establishment of distal metastases by cancer cells requires that the cells acquire a motile phenotype and the ability to survive, clonally expand, and recruit a blood supply. The functional interaction between tumor cells and the bone microenvironment is very important for the development of bone metastasis. Disruption of this interaction is a promising strategy that will allow the design of specific mechanism-based therapeutic interventions for bone metastases.Prostate cancer is the most common type of cancer in men and the second leading cause of cancer-related deaths in men in western countries. Currently available therapeutic modalities for prostate cancer, such as surgery, androgen ablation, radiation, and chemotherapy, have failed to cure patients with advanced disease. Matrix metalloproteinases (MMPs) are a large family of zinc-dependtent proteolytic enzymes that can cleave virtually any component of the extracellular matrix and play critical roles in the pathogenesis, especially formation of bone metastasis, of prostate cancer. The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that block the extracellular matrix-degrading activity of MMPs. We investigated the possibilities of genetically modifying human bones with TIMPs to create a high-TIMP bone microenvironment which is hostile to metastatic prostate cancer cells using adenovirus-mediated gene transfer technology. Two strategies were used to achieve bone-specific TIMP expression: ex vivo bone transduction and bone marrow stromal cell-mediated adenoviral transduction. In vitro, adenovirus-mediated expression of TIMP-1 or TIMP-2 in bone fragments inhibited MMP-2 activity, bone turnover, and prostate cancer cell (PC-3 and DU-145)-induced proteolytic degradation. In vivo, immunohistochemistry confirmed TIMP-2 expression in AdTIMP-2-infected bone implants 2 or 4 weeks after implantation in SCID mice. Mice receiving AdTIMP-treated bone fragments showed significantly reduced tumor growth and osteolysis by PC-3 cells and decreased bone turnover in the implanted bones. We propose that adenoviral gene transfer of TIMPs can prevent the metastatic spread of prostate cancer cells to bone and that enhancing anti-proteolytic defense mechanisms in target organs represents a promising form of prostate cancer gene therapy.Lung cancer is the leading cause of cancer death throughout the world, and is one of the most aggressive types of cancer. Lung cancer often metastasizes to bone in patients with advanced disease. We identified changes in metastasis-related gene expression of human HARA lung squamous carcinoma cells co-cultured with neonatal mouse calvariae using a pathway-specific microarray analysis. Nine genes were up-regulated and 2 genes down-regulated in HARA cells co-cultured with mouse calvariae. Five of the 9 up-regulated genes, including caveolin 1, CD44, EphB2, ezrin, and PTHrP, and 1 down-regulated gene, SLPI, were further confirmed by RT-PCR. A mouse model was subsequently used to study the role of PTHrP and ezrin in bone metastasis in vivo. PTHrP and ezrin were·up-regulated in. HARA cells at sites of bone metastasis compared to subcutaneous tumors as detected by RT-PCR and immunohistochemistry. Ezrin up-regulation was cog.firmed by western blots on HARA cells co-cultured with adult mouse long bones. Further, TGF-βwas identified as one of the factors in the bone microenvironment that was responsible for the up-regulation of ezrin. The idtentification of PTHrP and ezrin as important regulators of lung cancer bone metastasis offers new mechanistic insights, into the metastasis of lung cancer and provides potential targets for the prevention and treatment of lung cancer metastasis:Parathyroid hormone-related protein (PTHrP) is implicated in the control of bone remodeling and has both anabolic and catabolic effects on bone for unknown reasons. Suggested physiological roles for PTHrP include regulation of calcium transport, keratinocyte differentiation, smooth muscle relaxation, and cartilage development. The roles of PTHrP in tumorigenesis include regulation of malignant tumor cell growth and enhancement of cancer bone metastasis. Using in vitro mouse calvarial bone organ culture, we determined the role of PTHrP in new bone formation and bone destruction. We found that PTHrP produced from transfected breast cancer cells induced new bone formation at lower doses and bone destruction at higher concentration. The increased new bone formation was dependent on the .differentiation of osteoblasts and the induction of osteoprotegerin in osteoblasts but was not mediated through the endothelin receptor(s). These results provide direct evidence that PTHrP plays a biphasic role in bone remodeling depending on the concentration administered. This explains, at least in part, the different phenotypes of bone metastasis seen in lung and prostate cancers.

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