Abstract
We have previously shown that alendronate can prevent human PC-3 ML tumor cell metastasis to the bone (Wang and Stearns, 1991, Differentiation, 48, 115-25). In this paper, ELISAs and Western blots showed that TGF- β1 stimulated the secretion of a 72 kDa matrix metalloproteinase 2 (MMP-2) to enhance the solubilization of radiolabeled collagen 1 by metastatic human prostate PC-3 ML cells. A potent bisphos-phonate compound, alendronate, inhibited MMP-2 secretion to block solubilization of collagen 1. Alendronate failed to inhibit MMP-2 activity directly, but instead appeared to block cellular secretion of MMP-2. Alendronate failed to inhibit secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2; the inhibitor of MMP-2) and the decrease in collagen 1 solubilization observed may occur, in part, from changes in the molar stoichiometry of TIMP-2 to MMP-2. We conclude that alendronate may be a potent inhibitor of bone resorption based on its ability to block MMP-2 secretion by tumor cells. © Rapid Science Ltd.
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References
Berrettoni BA and Carter JR, 1986, Mechanisms of cancer metastasis to bone. J Bone Joint Surg, 68, 308-12.
Martin TJ and Mundy GR, 1987, Hypercalcemia of malignancy. In: Martin TJ and Raisz LG, eds. Clinical Endocrinology of Calcium Metabolism. New York: Marcel Dekker, pp. 171-99.
Nemoto R, Satou S, Miyagawa I and Koiso K, 1991, Inhibition by a new bisphosphonate (AHBuBp) of bone resorption induced by the MBT-2 tumor of mice. Cancer, 67, 643-8.
Manishen WJ, Sivananthan K and Orr FW, 1986, Resorbing bone stimulates tumor cell growth. A role for the host microenvironment in bone metastasis. Am J Pathol, 123, 39-45.
Canfield R, Rosner W, Skinner J et al. 1977, Diphosphonate therapy of Paget's disease of bone. J Clin Endocr Metab, 44, 96-106.
Fleisch H, 1987, Bisphosphonates - history and experimental basis. Bone, 8, 523-8.
Frijlink WB, Bijvoet OLM, de Veide J and Heynen G, 1979, Treatment of Paget's disease with (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate (APD). Lancet, 1, 799-803.
Merlini G, Parrinello GA, Piccinini L, et al. 1990, Longterm effects of parental dichloromethylene bisphosphonate (CL2MBP) on bone disease of myeloma patients treated with chemotherapy. Hematol Oncol, 3, 23-30.
Russel RGG, Smith R, Preston CJ, Walton RS and Woods CG, 1974, Diphosphonates in Paget's disease. Lancet, 1, 894-8.
Sanchez-Sweatman P, Khoka R, Singh G and Orr FW, 1996, Mechanisms of cancer cell mediated osteolysis. In: Orr GE and Singh F, eds. Bone Metastasis Mechanisms and Pathophysiology. Austin, Texas: R.G. Landes Co, pp. 123-32.
Smith R, Russel RGG and Bishop M, 1971, Diphosphonates and Paget's disease of bone. Lancet, 1, 945-7.
Attardo-Parrinello G, Merlini G, Pavesi F, Fiorentini ML and Ascari E, 1987, Effects of a new aminodiphosphonate in patients with osteolytic lesions from metastases and myelomatosis. Arch Intern Med, 147, 1629-33.
Elomaa I, Blomquist C, Porkka L et al. 1988, Clodronate for osteolytic metastases due to breast cancer. Biomed Pharmacother, 42, 111-16.
Hall DG and Stoica G, 1994, Effect of the bisphosphonate risedronate on bone metastases in a rat mammary adenocarcinoma model system. J Bone Min Res, 9, 221-30.
Morton AR, Cantrill JA, Pillai GV, McMahon A, Anderson DC and Howell A, 19??, Sclerosis of lytic bone metastases after disodium aminohydroxypropylidene bisphosphonate (APD) in patients with breast carcinoma. Br Med J, 297, 772-3.
Van Holten-Verzantvoort A, Bijvoet OLM, Cleton FJ, et al. 1987, Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet, 11, 983-5.
Rodan GA and Fleisch HA, 1996, Bisphosphonates: mechanisms of action. J Clin Invest, 97, 2692-6.
Cleton FJ, van Holten-Verzantvoort AT and Bijvoet OLM, 1989, Effect of long-term bisphosphonate treatment on morbidity due to bone metastases in breast cancer patients. In: Brunner KW, Fleisch H and Senn H-J, eds. Bisphosphonates and tumor osteolysis. Rec. Progr. Cancer Res. New York: Springer-Verlag, 116, 73-8.
Elte JWF, Bijvoet OLM, Cleton FJ, Van Oosterom AT and Sleeboom HP, 1986, Osteolytic bone metastases in breast carcinoma pathogenesis, morbidity and bisphosphonate treatment. Eur J Cancer Clin Oncol, 22493-500.
Fitton A and McTavish D, 1991, Pamidronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs, 41, 289-318.
Guaitani A, Sabatini M, Polentarutti N, et al. 1985, Effects of disodium etidronate on tumor-induced hypercalcemia, bone invasion, and metastasis in rodents. In: Garattini S, ed. Bone Resorption, Metastasis, and Diphosphonates. New York: Raven Press, pp. 51-8.
Jung A, Bornand J, Mermillod B, Edouard C and Meunier PJ, 1984, Inhibition by diphosphonates of bone resorption induced by the Walker tumor of the rat. Cancer Res, 44, 3007-11.
Shevrin DH, Gorny KI, Rosol TJ and Kukreja SC, 1991, Effect of etidronate disodium on the development of bone lesions in an animal model of bone metastasis using the human prostate cancer cell line PC-3. Prostate, 19, 149-54.
Clarke NW, McClure J and George NJ, 1992, Disodium pamidronate identifies differential osteoclastic bone resorption in metastatic prostate cancer. Br J Urol, 69, 64-70.
Averbuch SD, 1992, New bisphosphonates in the treatment of bone metastases. Cancer, 72, 3443-52.
Stearns ME and Wang M, 1996, Effects of alendronate and taxol on PC-3 ML cell bone metastases in SCID mice. Invas Metas, 16, 116-31.
Wang M and Stearns ME, 1991, Isolation and characterization of PC-3 human prostatic tumor sublines which preferentially metastasize to select organs in SCID mice. Differentiation, 48, 115-25.
Wang M, Fudge K, Rhim JS and Stearns ME, 1996, Cytokine regulation of the matrix metalloproteinases and their inhibitors in HPV-18 transformed human prostatic tumor cell lines. Oncol Res, 8, 303-15.
Stearns M and Stearns ME, 1996, Evidence for increased activated metalloproteinase 2 (MMP-2a) expression associated with human prostate cancer progression. Oncol Res, 8, 69-75.
Laemmli UK, 1970, Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680-5.
Towbin H, Staehelin T and Gordon J, 1979, Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets; procedures and some applications. Proc Natl Acad Sci USA, 76, 4350-4.
Bradford MM, 1976, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principles of protein-dye binding. Anal Biochem, 72, 248-54.
Hughes FJ and McCulloch CAG, 1991, Stimulation of the differentiation of osteogenic rat bone marrow stromal cells by osteoblast cultures. Lab Invest, 64, 617-22.
Levy AT, Cioce V, Sobel ME, et al. 1991, Increased expression of the mr 72,000 type IV collagenase in human colonic adenocarcinoma. Cancer Res, 51, 439-44.
Thiebaud D, Leyvraz S, von Fliedner V, et al. 1991, Treatment of bone metastases from breast cancer and myeloma with pamidronate. Eur J Cancer, 27, 37-41.
D'Errico A, Garbisa S, Liotta LA, Castronovo V, Stetler-Stevenson WG and Grigioni WF, 1991, Augmentation of type IV collagenase, laminin receptor, and Ki67 proliferation antigen associated with human colon, gastric and breast carcinoma progression. Mod Pathol, 4, 239-42.
Hewitt RE, Leach IH, Powe DG, Clark IM, Cawston TE and Turner DR, 1991, Distribution of collagenase and tissue inhibitor of metalloproteinases (TIMP) in colorectal tumours. Int J Cancer, 49, 666-72.
Irimura T, Yamora T, Bennett SC, Ota DM and Cleary KR, 1987, The relationship of collagenolytic activity to stage of human colorectal carcinoma. Int J Cancer, 40, 24-31.
Van Der Stappen JWJ, Hendriks T and Wobbes T, 1990, Correlation between collagenolytic activity and grade of histological differentiation in colorectal tumours. Int J Cancer, 45, 1071-8.
Lorenzo JA, Pilbeam CC, Kalinowski JF and Hibbs MS, 1992, Production of both 92 and 72 kDa gelatinases by bone cells. Matrix, 12, 282-90.
Monteagudo C, Merino MJ, San-Juan J, Liotta LA and Stetler-Stevenson WG, 1990, Immunohisto-chemical distribution of type IV collagenase in normal, benign and malignant breast tissue. Am J Pathol, 136, 585-92.
Stearns ME and Wang M, 1993, Type IV collagenase (Mr 72,000) expression in human prostate: benign and malignant tissue. Cancer Res, 53, 878-83.
Baron R, 1995, Molecular mechanisms of bone resorption. Acta Orthop Scand, 266, 66-70.
Carano A, Teitelbaum SL, Konsek JD, Schlesinger PH and Blair HC, 1990, Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J Clin Invest, 85, 456-61.
Everts V, Delaisse J-M, Korper W, Niehof A, Vaes G and Beertsen WJ, 1992, Degradation of collagen in the bone resorbing compartment underlying the osteoclast involves both systeine-proteinases and matrix metalloproteinase. Cell Physiol, 150, 221-31.
Hill PA, Docherty AJP, Bottomley KMK, et al. 1995, Inhibition of bone resorption in vitroby selective inhibitors of gelatinase and collagenase. Biochem J, 308, 167-75.
Chambers TJ and Fuller K, 1987, Generation of osteoclasts cultures of rabbit bone marrow and spleen cells. J Cell Physiol, 132, 441-52.
Meikle MC, Bord S, Hembry RM, Compston J, Croucher PI and Reynolds JJ, 1992, Human osteoblasts in culture synthesize collagenase and other matrix metalloproteinases in response to osteotropic hormones and cytokines. J Cell Sci, 103, 1093-9.
Rifas L, Halstead LR, Peck WA, Avioli LV and Welgus HG, 1989, Human osteoblasts in vitrosecrete tissue inhibitor of metalloproteinases and gelatinase but not interstitial collagenase as major cellular products. J Clin Invest, 84, 686-94.
Denhardt DT, Feng B, Dylan RE, Cocuzzi ET and Malyankar UM, 1993, Tissue inhibitor of metalloproteinases (TIMP, aka EPA): structure, control of expression and biological functions. Pharmac Ther, 59, 329-41.
Heath JK, Atkinson SJ, Meikle MC and Reynolds JJ, 1984, Mouse osteoblasts synthesize collagenase in response to bone resorbing agents. Biochim Biophys Acta, 802, 151-4.
Murphy G, McAlpine CG, Poll CT and Reynolds JJ, 1985, Purification and characterization of a bone metalloproteinase that degrades gelatin and types IV and V collagen. Biochim Biophys Acta, 831, 49-58.
Otsuka K, Sodek J and Limeback H, 1984, Synthesis of collagenase and collagenase inhibitors by osteoblast-like cells in culture. Eur J Biochem, 145, 123-9.
Shimizu H, Sakamoto M and Sakamoto S, 1990, Bone resorption by isolated osteoclasts in living versus devitalized bone: differences in mode and extent and the effects of human recombinant tissue inhibitor of metalloproteinase. J Bone Miner Res, 5, 411-18.
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Stearns, M.E. Alendronate blocks TGF-β1 stimulated collagen 1 degradation by human prostate PC-3 ML cells. Clin Exp Metastasis 16, 332–339 (1998). https://doi.org/10.1023/A:1006513413583
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DOI: https://doi.org/10.1023/A:1006513413583