OBJECTIVES: High tumor grade and lymph node positivity are associated with poor prognosis in breast carcinoma. Prognostic markers are used to define which patient groups benefit from different treatment modalities, some of which are potentially very toxic. Matrix metalloproteinases (MMPs) degrade the extracellular matrix, and type IV collagenases MMP-2 and -9 have been linked to invasive behavior of several malignancies. Tissue inhibitors of metalloproteinases (TIMPs) -1 and -2 inhibit their activity and are therefore considered to have an inhibitory effect on tumor progression. The role of TIMPs in progression of breast carcinoma is, however, still poorly known. Here the effect of TIMP-1 and -2 on survival was examined in lymph node-positive breast carcinoma patients. METHODS: TIMP-1 or -2 was evaluated with avidin-biotin immunohistochemical staining from paraffin-embedded sections of primary breast carcinoma of 132 cases. RESULTS: Positive staining for TIMP-1 and -2 was observed in 81 and 84% of the tumors respectively. TIMP-1 correlated to the grade of the tumor (p = 0.047). Absence of TIMP-1 protein correlated with favorable disease-specific survival of the patients with high-grade tumors. After 10 years of follow-up as high as 88% of patients with a grade 2-3, but TIMP-1-negative tumor were alive, when only 61% of the TIMP-1-positive cases in this group survived by that time (p = 0.03). CONCLUSION: Our results suggest that lack of TIMP-1 protein expression is associated with a favorable prognosis in patients with node-positive high-grade breast carcinoma.
To evaluate the biological roles and prognostic significance of the epithelial-mesenchymal transition (EMT)-mediating transcription factors (TFs) Twist, ZEB1 and Slug in patients with diffuse large B-cell lymphoma (DLBCL). EMT has been shown to enhance solid tumour metastasis, invasion, and proliferation.
Expression of Twist, ZEB1 and Slug was evaluated immunohistochemically in eight samples from reactive lymphoid tissues and in diagnostic samples from 102 DLBCL patients treated with curative intent with R-CHOP-type chemotherapy. ZEB1 and Slug expression correlated with adverse disease presentation. However, cytoplasmic Slug expression was linked to a favourable disease outcome, whereas nuclear expression of ZEB1 indicated an adverse outcome.
This study shows that an EMT-like process occurs in lymphomas. Of the TFs investigated, ZEB1 seems to be the main one associated with adverse clinical presentation and clinical outcome. Surprisingly, Slug expression in cytoplasm was linked to a favourable prognosis. Further studies are needed to evaluate whether inhibition of ZEB1 could serve as a therapeutic target.
Some molecular subtypes of breast cancer have preferential sites of distant relapse. The protein expression pattern of the primary tumor may influence the first distant metastasis site.
We identified from the files of the Finnish Cancer Registry patients diagnosed with breast cancer in five geographical regions Finland in 1991-1992, reviewed the hospital case records, and collected primary tumor tissue. Out of the 2,032 cases identified, 234 developed distant metastases after a median follow-up time of 2.7 years and had the first metastatic site documented (a total of 321 sites). Primary tumor microarray (TMA) cores were analyzed for 17 proteins using immunohistochemistry and for erbB2 using chromogenic in situ hybridization, and their associations with the first metastasis site were examined. The cancers were classified into luminal A, luminal B, HER2+ enriched, basal-like or non-expressor subtypes.
A total of 3,886 TMA cores were analyzed. Luminal A cancers had a propensity to give rise first to bone metastases, HER2-enriched cancers to liver and lung metastases, and basal type cancers to liver and brain metastases. Primary tumors that gave first rise to bone metastases expressed frequently estrogen receptor (ER) and SNAI1 (SNAIL) and rarely COX2 and HER2, tumors with first metastases in the liver expressed infrequently SNAI1, those with lung metastases expressed frequently the epidermal growth factor receptor (EGFR), cytokeratin-5 (CK5) and HER2, and infrequently progesterone receptor (PgR), tumors with early skin metastases expressed infrequently E-cadherin, and breast tumors with first metastases in the brain expressed nestin, prominin-1 and CK5 and infrequently ER and PgR.
Breast tumor biological subtypes have a tendency to give rise to first distant metastases at certain body sites. Several primary tumor proteins were associated with homing of breast cancer cells.
Cites: Cancer. 2011 May 1;117(9):1837-4621509760
Cites: Clin Cancer Res. 2008 Jul 1;14(13):4103-1018593987
OBJECTIVES: The influence of matrix-tumour interactions in Hodgkin's lymphoma is poorly characterised, although a large part of the tumour often consists of reactive tissue. The aim of the present study was to assess the clinicopathological role of two main inhibitors of matrix metalloproteinases, TIMP-1 and TIMP-2, in Hodgkin's lymphoma. MATERIALS AND METHODS: The TIMP-1 and TIMP-2 protein expressions were studied from paraffin-embedded tumour sections of 68 patients with Hodgkin's lymphoma by using immunostaining with TIMP-1 and TIMP-2-specific antibodies. The results of the stainings were compared with the clinicopathological disease characteristics. RESULTS: A total of 33.3% of the tumour tissue sections expressed TIMP-1 and 46.8% expressed TIMP-2. The expression of the TIMP-1 protein was found to be strongly associated with the nodular sclerosis subtype (P = 0.015) and the existence of a bulky tumour (P = 0.004) in Hodgkin's lymphoma. The expression of the TIMP-2 protein, on the other hand, correlated with the occurrence of B symptoms (P = 0.032). CONCLUSIONS: These results provide the first clinical evidence suggesting that TIMP-1 could promote growth of Hodgkin's lymphoma, and may be linked to connective tissue turnover in the nodular sclerosis subtype. However, TIMP-2 is shown to correlate with systemic symptoms.
Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor.
We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment.
We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months.
The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.
This is the first study to describe the role of MMP-2 and MMP-9 in Hodgkin's disease. Strong MMP-2 expression correlated with a favorable prognosis, while MMP-9 expression showed a tendency toward an adverse outcome. MMP-9 expression correlated with B symptoms and decreased new vessel formation. MMP-2 expression was associated with the nodular sclerosis subtype, and its expression was most pronounced in the vicinity of sclerosis. Neither of the gelatinases nor the extent of neovascularization correlated with tumor stage, the occurrence of bulky disease, or extranodal infiltrates. Together, these findings imply that the adverse role of MMP-9 may be associated with the controlling of immunological processes but not the invasion probabilities or neovascularization of the tumor. The favorable prognostic value of MMP-2 is surprising in view of the role of MMPs in solid tumors. This, however, may be linked to the basic biological differences of hematological malignancies vs. other tumors.
PURPOSE: Previous studies have shown that matrix metalloproteinase-9 (MMP-9) is expressed in malignant head and neck squamous cell carcinoma. The prognostic role of MMP-9 is still unclear. The aim of this study was to investigate the role of MMP-9 immunoreactive protein as a prognostic marker for survival in head and neck squamous cell carcinoma. EXPERIMENTAL DESIGN: Overexpression of the immunoreactive protein for MMP-9 was evaluated in tissue sections of 74 primary head and neck carcinomas with a monoclonal antibody using a biotin-streptavidin immunohistochemical staining method. The staining results were compared with the clinical data and to the patients' outcome. RESULTS: Positive immunostaining for MMP-9 was observed in 82% of the head and neck carcinomas, 39% of the cases being extensively positive. MMP-9 protein expression was independent of the stage or the grade of the tumor. The expression of MMP-9 was prognostic for shortened survival, the 5-year cause-specific survival being 45% in MMP-9 positive cases, and 92% in cases negative for MMP-9 (P = 0.013). MMP-9 positivity also correlated to the relapse-free survival (P = 0.019). At the 5-year follow-up, the cumulative relapse-free survival rate was 79% for patients with MMP-9-negative tumor and 42% for the patients with positive immunostaining for MMP-9. High expression of MMP-9 seemed to be linked with more aggressive relapses, appearing in 33% of the cases in local relapses, in 52% of cases with lymph node relapses, and in 60% of the cases with hematogenic relapses. CONCLUSIONS: This is the first study with a long follow-up showing that the immunoreactive protein of MMP-9 in head and neck carcinoma is associated with shortened relapse-free and cause-specific survival, suggesting that MMP-9 has a role in tumor progression of head and neck carcinomas, as well as in estimation of the prognosis of these diseases.
BACKGROUND: Potential tissue and serum biomarkers were assessed for predicting efficacy of bevacizumab in ovarian cancer (OC). PATIENTS AND METHODS: Twenty patients with OC received chemotherapy alone (control group) or in combination with bevacizumab (study group) in this non-randomised study. Pre- and post-treatment serum concentrations of vascular endothelial growth factor (VEGF), 8-hydroxydeoxyguanosine (8-OHdG) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured in all patients. In addition, immunohistochemical expressions VEGF receptors (R1, R2), hypoxia-inducible factor 1alpha (HIF-1 alpha), matrix metalloproteinases (-2, -9) and TIMP-2 were analysed in tumours from bevacizumab-treated patients. RESULTS: 8-OHdG and HIF-1alpha immunostainings were more highly expressed among patients with progression-free survival (PFS) >23 months than in patients with PFS
Matrix metalloproteinases (MMPs) have been linked to aggressive behavior in several malignancies. Gelatinases (MMP-2 and MMP-9) in particular are prognostic factors in many adeno- and epithelial cancers. However, no conclusive data exist concerning the role of gelatinases in endometrial cancer.
Eighty-eight patients with endometrial cancer, treated between 1988 and 1993 in Umeå University Hospital, were included. MMP-2 and MMP-9 proteins were analyzed immunohistochemically from paraffin-embedded tissues by using specific monoclonal antibodies. The staining results were compared to the clinical data.
Fifty-two percent of the cases were positive for MMP-9 and 72% for MMP-2. The overexpression of the proteins of either MMP-2 or MMP-9 was associated with poor survival. The predictive value of MMP-2 expression was most distinct in stage I cancers. An association was found between the positivity of MMP-2 and MMP-9. Only 3% of the cases were highly positive for both gelatinases and 18% of the cases were negative for both MMPs. Both gelatinases correlated to the histological grade. MMP-9 also correlated to the clinical stage of the disease, whereas MMP-2 did not. There was no apparent association with either depth of invasion, menopausal status, or the age of the patient.
MMP-2 and MMP-9 could serve as markers for the clinical behavior of endometrial cancer. They may further be linked to a tendency to cancer relapse. Thus, these gelatinases may turn out to be potentially useful in decision making about the need for an adjuvant treatment.
OBJECTIVES: The present study was carried out to clarify the role of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and the extent of neovascularization in the clinicopathologic behavior of non-Hodgkin's lymphomas. METHODS: Paraffin-embedded histologic sections from 57 patients with aggressive non-Hodgkin's lymphomas were stained with MMP-2, MMP-9, TIMP-1, and factor VIII antibodies to correlate the expression of these markers to the clinical disease characteristics. RESULTS: Strong MMP-9 staining was found to be an adverse prognostic factor among patients with aggressive B-cell lymphomas, the probabilities for 5-yr disease-free survival being 73%, 63%, 50%, and 0% in patients with grades 0, 1, 2, and 3 staining, respectively. Among the patients with strong (grades 2 and 3) MMP-9 staining, however, positivity for TIMP-1 indicated a trend toward a more favorable prognosis. TIMP-1 expression also correlated with the immunoblastic and anaplastic lymphoma subtypes. The expression of the proteins for MMP-2 and factor VIII had no independent prognostic role. None of the study parameters correlated with disease stage, the occurrence of extranodal infiltrates, the occurrence of bulky tumor, or the IPI scores. CONCLUSIONS: Positivity for MMP-9 immunoreactive protein is an independent sign of an unfavorable prognosis in non-Hodgkin's lymphomas. This is not mediated through influences in tumor dissemination or neovascularization indicating it to carry other important biological functions.