Abstract
Matrix metalloproteinases (MMPs) are essential in several stages of the metastatic process, and in normal bone development and remodeling. We explored whether the interaction between tumor cells and bone leads to changes in MMP and tissue inhibitor of MMP (TIMP) expression thus affecting osteolysis in metastatic bone disease. Using immunohistochemistry we have investigated the MMP/TIMP expression in tumor cells, fibroblasts, osteoblasts and osteoclasts. Thirty one specimens of bone metastasis from breast carcinoma were stained for MMP-1, -2, -9, MT1-MMP and TIMP- 1, and -2 and compared with staining in normal breast tissue, primary breast carcinoma and normal bone. Specimens came from patients in three clinical scenarios: from open biopsies without or with pathological fracture, or bone marrow biopsies containing tumor from patients with pancytopenia but without clinical evidence of osteolysis. By bone histomorphometry the latter group showed a heavy tumor load not different from the open biopsy groups but displayed little active bone resorption and low numbers of osteoclasts. Cell type-specific MMP/TIMP expression was observed and the staining patterns were comparable between the three groups of patients. Though no major differences in the MMP/TIMP staining of tumor cells and fibroblasts were observed between bone metastasis and primary tumor, we showed that tumor cells do express MMPs capable of degrading bone matrix collagen. The number and activity of osteoclasts and osteoblasts was increased dramatically in bone metastases, their MMP/TIMP profiles, however, were not different from normal bone, suggesting that the mechanism of bone degradation by osteoclasts is not different from normal bone remodelling.
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Mundy GR. Mechanisms of bone metastasis. Cancer 1997; 80: 1546–56.
Fuller K, Wong B, Fox S et al. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 1998; 188: 997–1001.
Taube T, Elomaa I, Blomqvist C et al. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone 1994; 15: 161–6.
Kulenkampff H-A, Dreyer T, Kersjes W et al. Histomorphometric analysis of osteoclastic bone resorption in metastatic bone disease from various primary malignomas. Virchows Arch A Pathol Anat Histopathol 1986; 409: 817–28.
Guise TA. Parathyroid hormone-related protein and bone metastases. Cancer 1997; 80: 1572–80.
Clohisy DR, Perkins SL, Ramnaraine MLR. Review of cellular mechanisms of tumor osteolysis. Clin Orthop Related Res 2000; 373: 104–14.
Miller LJ, Kurtzman SH, Anderson K et al. Interleukin-1 family expression in human breast cancer: Interleukin-1 receptor antagonist. Cancer Invest 2000; 18: 293–302.
Lacroix M, Siwek B, Marie PJ et al. Production and regulation of interleukin-11 by breast cancer cells. Cancer Lett 1998; 127: 29–35.
Fontanini G, Campani D, Roncella M et al. Expression of interleukin 6 (IL-6) correlates with oestrogen receptor in human breast carcinoma. Br J Cancer 1999; 80: 579–84.
Jimi E, Nakamura I, Duong LT et al. Interleukin-1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells. Exp Cell Res 1999; 247: 84–93.
Jimi E, Nakamura I, Ikebe T et al. Activation of NF-kB is involved in the survival of osteoclasts promoted by interleukin-1. J Biol Chem 1998; 273: 8799–805.
Drake FH, Dodds RA, James IE et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 1996; 271: 12511–6.
Bossard MJ, Tomaszek TA, Thompson SK et al. Proteolytic activity of human osteoclast cathepsin. J Biol Chem 1996; 271: 12517–24.
Powell WC, Matrisian LM. Complex roles of matrix metalloproteinases in tumor progression. Curr Top Microbiol Immunol 1996; 213: 1–21.
Blavier L, Henriet P, Imren S et al. Tissue inhibitors of matrix metalloproteinases in cancer. Ann NY Acad Sci 1999; 878: 108–19.
Lehti K, Lohi J, Valtanen H et al. Proteolytic processing of membrane-type-1 matrix metalloproteinase is associated with gelatinase A activation at the cell surface. Biochem J 1998; 334: 345–53.
Everts V, Delaissé JM, Korper W et al. Degradation of collagen in the bone-resorbing compartment underlying the osteoclast involves both cystein-proteinases and matrix metalloproteinases. J Cell Physiol 1992; 150: 221–31.
Chambers TJ, Fuller K. Bone cells predispose bone surfaces to resorption by exposure of mineral to osteoclastic contact. J Cell Sci 1985; 76: 155–65.
Vu TH, Shipley JM, Bergers G et al. MMP-9/Gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 1998; 93: 411–22.
Engsig MT, Chen Q-J, Vu TH et al. Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J Cell Biol 2000; 151: 878–89.
Holmbeck K, Bianco P, Caterina J et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 1999; 99: 81–92.
Parks WC. Matrix metalloproteinases in repair. Wound Rep Reg 1999; 7: 423–32.
Polette M, Gilles C, Marchand V et al. Tumor collagenase stimulatory factor (TCSF) expression and localization in human lung and breast cancers. J Histochem Cytochem 1997; 45: 703–9.
Ito A, Nakajima S, Sasaguri Y et al. Co-culture of human breast adenocarcinoma MCF-7 cells with human dermal fibroblasts enhances the production of matrix metalloproteinases 1, 2 and 3 in fibroblasts. Br J Cancer 1995; 71: 1039–45.
Kataoka H, DeCastro R, Zucker R et al. Tumor cell-derived collagenase-stimulatory factor increases expression of interstitial collagenase, stromelysin, and 72-kDa gelatinase. Cancer Res 1993; 53: 3154–8.
Duivenvoorden WCM, Lhotak S, Lee F et al. Bone metastasis in human breast and prostate cancer: Involvement of matrix metalloproteinases. Recent Res Devel Cancer 2000; 2: 115–41.
Parfitt AM. Bone histomorphometry: Standardization of nomenclature, symbols and units (summary of proposed system). Bone 1988; 9: 67–9.
Baker T, Tickle S, Wasan H et al. Serum metalloproteinases and their inhibitors: markers for malignant potential. Br J Cancer 1994; 70: 506–12.
Duffy MJ, McCarthy K. Matrix metalloproteinases in cancer: Prognostic marker and targets for therapy. Int J Oncol 1998; 12: 1343–8.
Kelly T, Børset M, Abe E et al. Matrix metalloproteinases in multiple myeloma. Leuk Lymph 2000; 37: 273–81.
Lein M, Jung K, Laube C et al. Matrix metalloproteinases and their inhibitors in plasma and tumor tissue of patients with renal cell carcinoma. Int J Cancer 2000; 85: 801–4.
Davies B, Waxman J, Wasan H et al. Levels of matrix metalloproteinase in bladder cancer correlate with tumor grade and invasion. Cancer Res 1993; 53: 5365–9.
Yu Q, Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 1999; 13: 35–48.
Meikle MC, Bord S, Hembry RM et al. Human osteoblasts in culture synthesize collagenase and other matrix metalloproteinases in response to osteotropic hormones and cytokines. J Cell Sci 1992; 103: 1093–9.
Lorenzo JA, Pilbeam CC, Kalinowski JF et al. Production of both 92-and 72-kDa gelatinases by bone cells. Matrix 1992; 12: 282–90.
Okada Y, Naka K, Kawamura K et al. Localization of matrix metalloproteinase 9 (92-kilodalton gelatinase/type IV collagenase=gelatinase B) in osteoclasts: Implications for bone resorption. Lab Invest 1995; 72: 311–21.
Bord S, Horner A, Beeton CA et al. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) distribution in normal and pathological human bone. Bone 1999; 24: 229–35.
Meikle MC, Bord S, Hembry RM et al. The synthesis of collagenase, gelatinase-A (72 kDa) and-B (95 kDa), and TIMP-1 and-2 by human osteoblasts from normal and arthritic bone. Bone 1995; 17: 255–60.
DeClerck YA, Perez N, Shimada H et al. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 1992; 52: 701–8.
Albini A, Melchiori A, Santi L et al. Tumor cell invasion inhibited by TIMP-2. J Natl Cancer Inst 1991; 83: 775–9.
Grigioni WF, D'Errico A, Fortunato C et al. Prognosis of gastric carcinoma revealed by the interactions between tumor cells and basement membrane. Mod Pathol 1994; 7: 220–5.
Wagner SN, Ockenfels HM, Wagner C et al. Differential expression of tissue inhibitor of metalloproteinase-2 by cutaneous squamous and basal cell carcinomas. J Invest Dermatol 1996; 106: 321–6.
Ree AH, Flørenes VA, Berg JP et al. High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases. Clin Cancer Res 1997; 3: 1623–8.
Visscher DW, Höyhtyä M, Ottosen SK et al. Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. Int J Cancer 1994; 59: 339–44.
Hill PA, Reynolds JJ, Meikle MC. Inhibition of stimulated bone resorption in vitro by TIMP-1 and TIMP-2. Biochim Biophys Acta 1993; 1177: 71–4.
Yoneda T, Sasaki A, Dunstan C et al. Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate Ibandronate and tissue inhibitor of the matrix metalloproteinase-2. J Clin Invest 1997; 99: 2509–17.
Shibutani T, Yamashita K, Aoki T et al. Tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2) stimulate osteoclastic bone resorption. J Bone Miner Metab 1999; 17: 245–51.
Hayakawa T, Yamashita K, Ohuchi E et al. Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J Cell Sci 1994; 107: 2373–9.
Yamagiwa H, Tokunaga K, Hayami T et al. Expression of metalloproteinase-13 (Collagenase-3) is induced during fracture healing in mice. Bone 1999; 25: 197–203.
Rowinsky EK, Humphrey R, Hammond LA et al. Phase I and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12-9566 on a protracted oral daily dosing schedule in patients with solid malignancies. J Clin Oncol 2000; 18: 178–86.
Bramhall SR. Stromal degradation by the malignant epithelium in pancreatic cancer and the therapeutic potential of proteolytic inhibition. J Hepatobiliary Pacreat Surg 1998; 5: 392–401.
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Lhoták, Š., Elavathil, L.J., Vukmirović-Popović, S. et al. Immunolocalization of matrix metalloproteinases and their inhibitors in clinical specimens of bone metastasis from breast carcinoma. Clin Exp Metastasis 18, 463–470 (2000). https://doi.org/10.1023/A:1011800919981
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DOI: https://doi.org/10.1023/A:1011800919981