Prospective evaluation of serum tissue inhibitor of metalloproteinase-1 (TIMP-1) and carbonic anhydrase IX (CAIX) in correlation to circulating tumor cells in patients with metastatic breast cancer.

Introduction: Circulating tumor cells (CTCs) reflect aggressive tumor behavior by hematogenous tumor cell dissemination. The tissue inhibitor of metalloproteinase 1 (TIMP-1) plays a role in tissue invasion and is also involved in angiogenesis, abrogation of apoptosis and in chemoresistance. Carbonic anhydrase IX (CAIX) is a metalloenzyme involved in cell adhesion, growth and survival of tumor cells. The aim of the study was to investigate whether serum concentrations of TIMP-1 and CAIX are associated with the detection of CTC in metastatic breast cancer. Methods: Blood was obtained in a prospective multicenter setting from 253 patients with metastatic breast cancer at the time of disease progression. Serum TIMP-1 and CAIX were determined using commercial ELISA-kits (Oncogene Science). CTC were detected with the CellSearch™ system (Veridex). Results: Five or more CTCs were detected in 122 patients out of 245 evaluable patients (49.8%). Out of 253 metastatic patients 70 (28%) had serum TIMP-1 levels above 454 ng/mL. Serum CAIX was elevated above 506 ng/ mL in 90 (35%) patients. Both serum markers had prognostic significance. Median progression free survival (PFS) was 7.2 months with elevated TIMP-1 vs. 11.4 months with non-elevated levels (p < 0.01). OS was 11.5 vs. 19.1 months (p < 0.01). Median PFS was 7.5 months with elevated CAIX vs. 11.7 months with non-elevated levels (p < 0.01), overall survival (OS) was 13.4 months vs. 19.1 months (p < 0.01). In patients with five or more CTCs, serum levels were above the cut-off for CAIX in 47% vs. 25% in those with less than five CTCs (p = 0.01). For TIMP-1, 37% patients with five or more CTCs had elevated serum levels and 17% of patients with less than five CTCs (p = 0.01). Including TIMP-1, CAIX, CTC and established prognostic factors in the multivariate analysis, the presence of CTCs, the therapy line and elevated CAIX remained independent predictors of OS. Conclusions: Elevated serum levels of the invasion markers TIMP-1 and CAIX in metastatic breast cancer are prognostic markers and are associated with the presence of CTCs. Whether increased secretion of TIMP-1 and/or CAIX might directly contribute to tumor cell dissemination remains to be elucidated in further investigations.

[1]  S. Leung,et al.  Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. , 2011, Cancer research.

[2]  Max S Wicha,et al.  Circulating tumor cells: not all detected cells are bad and not all bad cells are detected. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Y. Li,et al.  Catalysis and pH Control by Membrane-associated Carbonic Anhydrase IX in MDA-MB-231 Breast Cancer Cells* , 2011, The Journal of Biological Chemistry.

[4]  A. Harris,et al.  New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation , 2010, Oncogene.

[5]  N. Brünner,et al.  Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells--associations with histopathology and patients outcome. , 2010, European journal of cancer.

[6]  T. Fehm,et al.  HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial , 2010, Breast Cancer Research and Treatment.

[7]  R. Simon,et al.  Overexpression of carbonic anhydrase IX (CAIX) in vulvar cancer is associated with tumor progression and development of locoregional lymph node metastases , 2010, Virchows Archiv.

[8]  B. Monk,et al.  Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: a Gynecologic Oncology Group study. , 2010, Gynecologic oncology.

[9]  Nils Brünner,et al.  HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  Xiongfei Zhang,et al.  Tissue inhibitor of metalloproteinase‐1 protects MCF‐7 breast cancer cells from paclitaxel‐induced apoptosis by decreasing the stability of cyclin B1 , 2010, International journal of cancer.

[11]  N. Brünner,et al.  Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer , 2010, Breast Cancer Research and Treatment.

[12]  W. Carney,et al.  TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients , 2010, BMC Cancer.

[13]  Andrea Scozzafava,et al.  Inhibition of carbonic anhydrase IX: a new strategy against cancer. , 2009, Anti-cancer agents in medicinal chemistry.

[14]  C. Supuran,et al.  Carbonic anhydrase inhibitors. Biphenylsulfonamides with inhibitory action towards the transmembrane, tumor-associated isozymes IX possess cytotoxic activity against human colon, lung and breast cancer cell lines , 2009 .

[15]  A. Belldegrun,et al.  Carbonic anhydrase IX in bladder cancer , 2009, Cancer.

[16]  S. Fox,et al.  The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy , 2009, British Journal of Cancer.

[17]  J. Cardelli,et al.  TIMP-1 overexpression promotes tumorigenesis of MDA-MB-231 breast cancer cells and alters expression of a subset of cancer promoting genes in vivo distinct from those observed in vitro , 2009, Breast Cancer Research and Treatment.

[18]  Robert A Gatenby,et al.  Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. , 2008, Seminars in cancer biology.

[19]  Sabine Riethdorf,et al.  Circulating Tumor Cells and Bone Marrow Micrometastasis , 2008, Clinical Cancer Research.

[20]  J. Tostain,et al.  Serum carbonic anhydrase 9 level is associated with postoperative recurrence of conventional renal cell cancer. , 2008, The Journal of urology.

[21]  I. Christensen,et al.  A Comparative Study of Tissue Inhibitor of Metalloproteinases-1 Levels in Plasma and Tumour Tissue from Patients with Primary Breast Cancer and in Plasma from Patients with Metastatic Breast Cancer , 2008, Tumor Biology.

[22]  W. Carney,et al.  Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  N. Brünner,et al.  TIMP-1 as a tumor marker in breast cancer – An update , 2008, Acta oncologica.

[24]  H. Nielsen,et al.  Comparative studies of tissue inhibitor of metalloproteinases-1 in plasma, serum and tumour tissue extracts from patients with primary colorectal cancer , 2008, Scandinavian journal of gastroenterology.

[25]  J. Thiery,et al.  Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[26]  P. Maini,et al.  Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer , 2007, British Journal of Cancer.

[27]  Robert J Gillies,et al.  Glycolysis in cancer: a potential target for therapy. , 2007, The international journal of biochemistry & cell biology.

[28]  W. Carney,et al.  Elevated plasma tissue inhibitor of metalloproteinase‐1 level predicts decreased response and survival in metastatic breast cancer , 2007, Cancer.

[29]  W. Carney.  Circulating oncoproteins HER2/neu, EGFR and CAIX (MN) as novel cancer biomarkers , 2007, Expert review of molecular diagnostics.

[30]  Brigitte Rack,et al.  Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System , 2007, Clinical Cancer Research.

[31]  D. Rea,et al.  Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer , 2007, British Journal of Cancer.

[32]  N. Brünner,et al.  Primary Tumor Levels of Tissue Inhibitor of Metalloproteinases-1 Are Predictive of Resistance to Chemotherapy in Patients with Metastatic Breast Cancer , 2006, Clinical Cancer Research.

[33]  R. Millikan,et al.  CA IX is an Independent Prognostic Marker in Premenopausal Breast Cancer Patients with One to Three Positive Lymph Nodes and a Putative Marker of Radiation Resistance , 2006, Clinical Cancer Research.

[34]  G. T. Budd,et al.  Circulating Tumor Cells at Each Follow-up Time Point during Therapy of Metastatic Breast Cancer Patients Predict Progression-Free and Overall Survival , 2006, Clinical Cancer Research.

[35]  D. Hayes,et al.  New guidelines for reporting of tumor marker studies in breast cancer research and treatment: REMARK , 2006, Breast Cancer Research and Treatment.

[36]  W. Sauerbrei,et al.  Reporting recommendations for tumor marker prognostic studies (REMARK). , 2005, Journal of the National Cancer Institute.

[37]  Adrian L Harris,et al.  Role of Carbonic Anhydrase IX in Human Tumor Cell Growth, Survival, and Invasion , 2004, Cancer Research.

[38]  Alison Stopeck,et al.  Circulating tumor cells, disease progression, and survival in metastatic breast cancer. , 2004, The New England journal of medicine.

[39]  C. Luparello,et al.  Tissue inhibitor of metalloprotease (TIMP)‐1 and proliferative behaviour of clonal breast cancer cells , 1999, Breast Cancer Research and Treatment.

[40]  Xu-wen Liu,et al.  Tissue Inhibitor of Metalloproteinase-1 Protects Human Breast Epithelial Cells Against Intrinsic Apoptotic Cell Death via the Focal Adhesion Kinase/Phosphatidylinositol 3-Kinase and MAPK Signaling Pathway* , 2003, Journal of Biological Chemistry.

[41]  Klaus Pantel,et al.  Molecular signature associated with bone marrow micrometastasis in human breast cancer. , 2003, Cancer research.

[42]  J. Závada,et al.  Soluble form of carbonic anhydrase IX (CA IX) in the serum and urine of renal carcinoma patients , 2003, British Journal of Cancer.

[43]  Donna Richardson,et al.  Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  Steve Horvath,et al.  Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[45]  Kerry S. Smith,et al.  Carbonic Anhydrase: New Insights for an Ancient Enzyme* 210 , 2001, The Journal of Biological Chemistry.

[46]  A. Harris,et al.  Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. , 2001, Cancer research.

[47]  W. Sly,et al.  Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. , 2001, The American journal of pathology.

[48]  P H Watson,et al.  Hypoxia-inducible expression of tumor-associated carbonic anhydrases. , 2000, Cancer research.

[49]  G. Li,et al.  Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. , 1999, Cancer research.

[50]  K. Zeller,et al.  Function of the c-Myc oncogenic transcription factor. , 1999, Experimental cell research.

[51]  Z. Werb,et al.  Rescue of mammary epithelial cell apoptosis and entactin degradation by a tissue inhibitor of metalloproteinases-1 transgene , 1996, The Journal of cell biology.

[52]  K. Iwata,et al.  Growth‐promoting activity of tissue inhibitor of metalloproteinases‐1 (TIMP‐1) for a wide range of cells A possible new growth factor in serum , 1992, FEBS letters.