Abstract
Purpose
Matrix metalloproteinases are responsible for proteolytic degradation of basement membrane and extracellular matrix. In tumor tissues, elevated expression of matrix metalloproteinase-1 (MMP-1) has been associated with tumor invasion and metastasis. However, little is known about the expression of MMP-1 in peripheral blood (PB) and bone marrow (BM) in gastric cancer patients. Thus, the aim of the present study is to determine MMP-1 messenger RNA (mRNA) expression levels in BM and PB of patients with gastric cancer.
Methods
The study group consisted of 857 patients with gastric cancer (577 males and 280 females) ranging in age from 27 to 87 years (average 61.6 years). MMP-1 mRNA expression levels in BM and PB were evaluated quantitatively by real-time reverse-transcription polymerase chain reaction (RT-PCR).
Results
Expression of MMP-1 mRNA in BM and PB of patients with gastric cancer was significantly higher than in noncancer patients. High levels of MMP-1 mRNA expression were significantly associated with differentiated histology, tumor size, tumor invasiveness, lymph node metastasis, liver metastasis, and clinical stage. Particularly importantly, MMP-1 mRNA expression in PB was an independent factor of distant metastasis.
Conclusions
We disclosed that MMP-1 mRNA expression in peripheral blood and bone marrow of gastric cancer patients was very high, precisely reflecting staging of gastric cancer. MMP-1 mRNA expression in peripheral blood may be a useful marker for distant metastasis in gastric cancer.
Similar content being viewed by others
References
Braun S, Vogl FD, Naume B, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005; 353: 793–802.
Pantel K, Woelfle U. Micrometastasis in breast cancer and other solid tumors. J Biol Regul Homeost Agents. 2004; 18: 120–5.
Seeliger H, Spatz H, Jauch KW. Minimal residual disease in gastric cancer. Recent Results Cancer Res. 2003; 162: 79–87.
Vogel I, Kalthoff H. Disseminated tumour cells. Their detection and significance for prognosis of gastrointestinal and pancreatic carcinomas. Virchows Arch. 2001; 439: 109–17.
Tsavellas G, Patel H, Allen-Mersh TG. Detection and clinical significance of occult tumour cells in colorectal cancer. Br J Surg. 2001; 88: 1307–20.
Bockmann B, Grill HJ, Giesing M. Molecular characterization of minimal residual cancer cells in patients with solid tumors. Biomol Eng. 2001; 17: 95–111.
Braun S, Pantel K. Micrometastatic bone marrow involvement: detection and prognostic significance. Med Oncol. 1999; 16: 154–65.
Calaluce R, Miedema BW, Yesus YW. Micrometastasis in colorectal carcinoma: a review. J Surg Oncol. 1998; 67: 194–202.
Iinuma H, Okinaga K, Egami H, et al. Usefulness and clinical significance of quantitative real-time RT-PCR to detect isolated tumor cells in the peripheral blood and tumor drainage blood of patients with colorectal cancer. Int J Oncol. 2006; 28: 297–306.
Mimori K, Fukagawa T, Kosaka Y, et al. Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1. Clin Cancer Res. 2008; 14: 2609–16.
Heiss MM, Simon EH, Beyer BC, et al. Minimal residual disease in gastric cancer: evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow. J Clin Oncol. 2002; 20: 2005–16.
Heiss MM, Allgayer H, Gruetzner KU, Babic R, Jauch KW, Schildberg FW. Clinical value of extended biologic staging by bone marrow micrometastases and tumor-associated proteases in gastric cancer. Ann Surg. 1997; 226: 736–44; discussion 744–735.
Heiss MM, Allgayer H, Gruetzner KU, et al. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nat Med. 1995; 1: 1035–9.
Blasi F. Urokinase and urokinase receptor: a paracrine/autocrine system regulating cell migration and invasiveness. Bioessays. 1993; 15: 105–11.
Duffy MJ. The role of proteolytic enzymes in cancer invasion and metastasis. Clin Exp Metastasis. 1992; 10: 145–55.
Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991; 64: 327–36.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002; 2: 161–74.
Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001; 17: 463–516.
Brinckerhoff CE, Rutter JL, Benbow U. Interstitial collagenases as markers of tumor progression. Clin Cancer Res. 2000; 6: 4823–30.
Shiozawa J, Ito M, Nakayama T, Nakashima M, Kohno S, Sekine I. Expression of matrix metalloproteinase-1 in human colorectal carcinoma. Mod Pathol. 2000; 13: 925–33.
Kanamori Y, Matsushima M, Minaguchi T, et al. Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res. 1999; 59: 4225–7.
Ito T, Ito M, Shiozawa J, Naito S, Kanematsu T, Sekine I. Expression of the MMP-1 in human pancreatic carcinoma: relationship with prognostic factor. Mod Pathol. 1999; 12: 669–74.
Murray GI, Duncan ME, O’Neil P, McKay JA, Melvin WT, Fothergill JE. Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer. J Pathol. 1998; 185: 256–61.
Murray GI, Duncan ME, O’Neil P, Melvin WT, Fothergill JE. Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer. Nat Med. 1996; 2: 461–62.
Nakopoulou L, Giannopoulou I, Gakiopoulou H, Liapis H, Tzonou A, Davaris PS. Matrix metalloproteinase-1 and -3 in breast cancer: correlation with progesterone receptors and other clinicopathologic features. Hum Pathol. 1999; 30: 436–42.
Inoue T, Yashiro M, Nishimura S, et al. Matrix metalloproteinase-1 expression is a prognostic factor for patients with advanced gastric cancer. Int J Mol Med. 1999; 4: 73–7.
Airola K, Karonen T, Vaalamo M, et al. Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas. Br J Cancer. 1999; 80: 733–43.
Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997; 80: 1803–4.
Masuda TA, Inoue H, Sonoda H, et al. Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. Cancer Res. 2002; 62: 3819–25.
Mori M, Mimori K, Inoue H, et al. Detection of cancer micrometastases in lymph nodes by reverse transcriptase-polymerase chain reaction. Cancer Res. 1995; 55: 3417–20.
Sasse EA. How to define and determine reference intervals in the clinical laboratory: approved guideline. 2000.
Sugai H, Kono K, Takahashi A, et al. Characteristic alteration of monocytes with increased intracellular IL-10 and IL-12 in patients with advanced-stage gastric cancer. J Surg Res. 2004; 116: 277–87.
Beerepoot LV, Mehra N, Vermaat JS, Zonnenberg BA, Gebbink MF, Voest EE. Increased levels of viable circulating endothelial cells are an indicator of progressive disease in cancer patients. Ann Oncol. 2004; 15: 139–45.
Mancuso P, Burlini A, Pruneri G, Goldhirsch A, Martinelli G, Bertolini F. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood. 2001; 97: 3658–61.
Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci USA. 2000; 97: 14608–13.
Beaudry P, Force J, Naumov GN, et al. Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity. Clin Cancer Res. 2005; 11: 3514–22.
Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest. 2000; 105: 71–7.
Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275: 964–7.
Peters BA, Diaz LA, Polyak K, et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med. 2005; 11: 261–2.
Barille S, Collette M, Thabard W, Bleunven C, Bataille R, Amiot M. Soluble IL-6R alpha upregulated IL-6, MMP-1 and MMP-2 secretion in bone marrow stromal cells. Cytokine. 2000; 12: 1426–9.
Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature. 1980; 284: 67–8.
Kosaka Y, Mimori K, Fukagawa T, et al. Identification of the high-risk group for metastasis of gastric cancer cases by vascular endothelial growth factor receptor-1 overexpression in peripheral blood. Br J Cancer. 2007; 96: 1723–8.
Acknowledgment
We thank Miss T. Shimooka, Mrs. K. Ogata, Miss M. Oda, Miss N. Kasagi, and Miss Y. Nakagawa for their excellent technical assistance. Grant support: CREST, Japan Science and Technology Agency (JST); Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research, grant numbers 17109013, 17591411, 17591413, 18390367, 18590333, 18659384, and 18790964; The Ministry of Education, Culture, Sports, Science, and Technology (MEXT) Grant-in-Aid for Scientific Research on Priority Areas, grant number 18015039.
Author information
Authors and Affiliations
Corresponding author
Additional information
Mitsuru Sasako and Masaki Mori contributed equally to this work.
Rights and permissions
About this article
Cite this article
Kosaka, Y., Mimori, K., Fukagawa, T. et al. Clinical Significance of Molecular Detection of Matrix metalloproteinase-1 in Bone Marrow and Peripheral Blood in Patients with Gastric Cancer. Ann Surg Oncol 19 (Suppl 3), 430–437 (2012). https://doi.org/10.1245/s10434-011-1905-y
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-011-1905-y