OBJECTIVETo evaluate the immunophenotype conversion of fibroblasts and its clinical significance in the process of breast tumor stromal remodeling.

METHODSCD34, FAP-α, p63 and a-SMA were detected by immunohistochemistry in 273 breast biopsies, including 60 normal breast tissues, 46 atypical ductal hyperplasia (ADH), 60 ductal carcinoma in situ (DCIS), 47 DCIS microinvasive carcinoma (DCIS-MI) and 60 invasive ductal carcinoma (IDC).

RESULTSThe positive expression rates of CD34, FAP-α and α-SMA in the stromal fibroblasts of normal breast tissues were 93.3%, 6.7% and 18.3%, respectively. Those in the stromal fibroblasts of ADH tissues were 95.7%, 4.3% and 10.9%, respectively. Those in the stromal fibroblasts of DCIS tissues were 95.0%, 8.3% and 15.0%, respectively. Those in the IDC tissues were 35.0%, 85.0% and 93.3%, respectively. The expressions of CD34, α-SMA and FAP-α in the stromal fibroblasts of normal, ASH and DCIS breast tissues did not show significant differences (χ(2) = 1.142, P = 0.896). The main immunophenotype of stromal fibroblasts in the tumor-host interface at the invasive front of ADH and DCIS lesions was CD34(+)α-SMA(+)FAP-α(+). There were statistically significant differences in the expression of CD34, α-SMA and FAP-α between IDC and ADH, DCIS and normal breast tissues (χ(2) = 8.351, P < 0.001). The immunophenotype of stromal fibroblasts in the IDC and DCIS-MI breast tissues was CD34(-) α-SMA(+) FAP-α(+).

CONCLUSIONSImmunophenotype conversion from CD34(+) α-SMA(-) FAP-α(-) to CD34(-) α-SMA(+)FAP-α(+) may be a sensitive indicator to judge whether DCIS has microinvasion. Detection of the immunophenotype conversion of stromal fibroblasts may be helpful to determine the presence of microinvasion, and to improve the diagnostic accuracy rate of DCIS.

Breast ; Breast Neoplasms ; immunology ; pathology ; Carcinoma in Situ ; Carcinoma, Ductal, Breast ; Carcinoma, Intraductal, Noninfiltrating ; Fibroblasts ; immunology ; Gelatinases ; metabolism ; Humans ; Hyperplasia ; Immunohistochemistry ; Immunophenotyping ; Membrane Proteins ; metabolism ; Serine Endopeptidases ; metabolism

Increased production of matrix metalloproteinases (MMPs) has been associated with increases in invasive and metastatic potential in many types of human carcinoma. Tissue inhibitors of metalloproteinase (TIMP)-1 inhibits most interstitial collagenases and MMP-9. TIMP-2 binds specifically and noncovalently to the pro-form of MMP-2 and inhibits its enzyme activity. In this study, we examined TIMP-1 and TIMP-2 expressions in relation to clinicopathological variables in colorectal carcinoma with in situ hybridization and immunohistochemistry. TIMP-1 and TIMP-2 expressions were localized overwhelmingly to pericancer stromal cells, while malignant and normal mucosal cells were weak or negative. Strong stromal TIMP-1 immunoreactivity correlated with Dukes' stage (p=0.022), status of lymph node metastasis (p=0.044) and poor survival (p= 0.005). The degree of immunohistochemical staining of TIMP-2 did not correlate with all clinicopathological variables. The correlation between enhanced TIMP-1 expression and advanced stage and poor survival suggest a growth promoting activity of TIMP-1 in colorectal carcinoma.
Adenocarcinoma/pathology ; Adenocarcinoma/mortality ; Adenocarcinoma/enzymology* ; Adult ; Aged ; Aged, 80 and over ; Antibodies ; Collagenases/immunology ; Collagenases/genetics* ; Collagenases/analysis ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/enzymology* ; DNA Probes ; Female ; Gelatinase A ; Gelatinase B ; Gelatinases/immunology ; Gelatinases/genetics* ; Gelatinases/analysis ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Human ; In Situ Hybridization ; Male ; Metalloendopeptidases/immunology ; Metalloendopeptidases/genetics* ; Metalloendopeptidases/analysis ; Middle Age ; Predictive Value of Tests ; RNA, Messenger/analysis ; Stromal Cells/pathology ; Stromal Cells/enzymology ; Survival Analysis ; Tissue Inhibitor-of Metalloproteinase-2/immunology ; Tissue Inhibitor-of Metalloproteinase-2/genetics* ; Tissue Inhibitor-of Metalloproteinase-2/analysis ; Tissue-Inhibitor of Metalloproteinase-1/immunology ; Tissue-Inhibitor of Metalloproteinase-1/genetics* ; Tissue-Inhibitor of Metalloproteinase-1/analysis

Chlamydia pneumoniae infection implicated as an important etiologic factor of atherosclerosis, especially in coronary artery disease (CAD), was found in vitro to be associated with the induction of matrix metalloproteinases (MMPs). An extracellular matrix metalloproteinase inducer (EMMPRIN)/membrane-type 1 matrix metalloproteinase (MT1-MMP) system which induces and activates MMPs,is suggested to be functional and were upregulated in the failing myocardium. However, the upstream regulation of MMPs by C. pneumoniae within atheroma itself remains unclear. We evaluated the seroepidemiologic study of C. pneumoniae infection in CAD patients (n = 391) and controls (n = 97) and performed histopathological and in vitro analysis in atherosclerotic vascular tissues obtained from patients with seropositive to C. pneumoniae (n = 20), by using immunochemistry for C. pneumoniae, EMMPRIN/MT1-MMP, MMP-2, and MMP-9. The seropositive rates of both anti-C. pneumoniae IgG and IgA were 56.7% in CAD group and 43.3% in control group (P =0.033). Seropositive rate was increased in subgroups of CAD patients without conventional coronary risk factors compared to those with conventional risk factors. Immunoreactivities of EMMPRIN, MT1-MMP, MMP-2, and MMP-9 were increased in the atheromatous plaque itself, predominantly in immunoreactive macrophages/mononuclear cells to C. pneumoniae. Furthermore, Western blot analysis showed that EMMPRIN and MMP-2 were detected more prominently in atherosclerotic tissues infected with C. pneumoniae compared to control tissues. Zymographic analysis revealed that activities of MMP-2 and MMP-9 were more increased in atherosclerotic tissues infected with C. pneumoniae compared to control tissues. The present study demonstrated upstream regulation of MMPs can be induced by C. pneumoniae within atheromatous plaque itself. These findings help to understand the potential role of C. pneumoniae in the progression of atherosclerosis.
Aged ; Animals ; Arteriosclerosis/complications/enzymology/*microbiology/*pathology ; Blotting, Western ; Chlamydia Infections/*complications/enzymology/epidemiology/immunology ; Chlamydophila pneumoniae/immunology/*pathogenicity ; Disease Progression ; Extracellular Matrix/enzymology ; Female ; Gelatinases/*metabolism ; Human ; Immunohistochemistry ; Male ; Matrix Metalloproteinases/*metabolism ; Membrane Glycoproteins/*metabolism ; Middle Aged ; Up-Regulation