The 72-kDa (MMP-2, gelatinase A) and the 92-kDa (MMP-9, gelatinase B) matrix metalloproteinases have been associated with tumor cell invasion and metastasis. Immunohistological staining of MMP-2 and MMP-9, basal lamina collagen IV and TIMP-2 were performed on frozen sections of 83 invasive breast carcinomas. MMP-2 and MMP-9 were associated with neoplastic cell plasma membrane in 72% of cases and exhibited inter-tumoral variability of staining intensity. MMP-2 and MMP-9 staining was not correlated with presence of metastases at time of diagnosis or with disease outcome. TIMP-2 was detected in the peri-tumoral stroma and was present in 87% of cases. Residual benign breast tissue was negative for TIMP-2 staining. Neoplasms with diffuse TIMP-2 staining (24%) recurred significantly more frequently (75% recurred) than cases with focal (42% recurred) or absent (27% recurred) TIMP-2. Presence of collagen IV was negatively correlated with gelatinase staining. We conclude that up-regulation of MMP-2 and MMP-9 expression in breast tumor cells is reciprocally correlated to collagen IV staining. Clinical outcome, however, is more closely related to the presence of TIMP-2 than the corresponding MMPs. Enhanced TIMP-2 expression, therefore, may denote a stromal response to tumor invasion, indicative of aggressive behavior in a subset of breast carcinomas.
Breast carcinomas often contain multiple DNA stemlines in flow cytometric DNA histograms. However, due to mixing during tissue disaggregation the microanatomical relationship between the cells which comprise distinct stemlines is unclear. We performed image cytophotometric DNA analysis (IA) on two separate areas of intact tissue sections of 19 breast carcinomas which were selected on the basis of flow cytometric (FCM) DNA content heterogeneity (i.e., multiple stemlines). For comparison, similar analyses were performed on seven tumors with unimodal FCM DNA histograms. Six of the 7 tumors (86%) with unimodal FCM histograms were also unimodal in both IA DNA histograms. Among tumors with heterogeneous FCM DNA histograms, the presence of multiple stemlines was confirmed in IA DNA histograms in 16/19. In nine of these 16 cases, multiple DNA stemlines having similar DNA indices were present in both areas of neoplasm examined with IA. The remaining seven cases displayed unimodal LA histograms in both areas, however DNA indices differed between the two histograms. These frndings imply that cell populations corresponding to flow cytometrically detected DNA stemlines are often intimately admixed, even within geographically separated portions of breast tumors. This pattern suggests that productive interactions between genetically distinct tumor populations may lead to stable co-dominance of ancestral clones during progression of some breast Carcinomas. 0 1995 Wiley-Liss, Inc.Key terms: Breast carcinoma, tumor heterogeneity, DNA analysis Adult epithelial malignancies, such as breast carcinomas, frequently demonstrate multiple stemlines in cytophotometric DNA histograms. These stemlines are presumed to represent ancestrally related clonal populations (2,7,1O). Very little is known about the morphologic changes which accompany evolving clones, or the geographic relationships between genetically-distinct populations of tumor cells. This is because analysis of clonality is generally performed either at the molecular level or o n dissociated cell samples, which obscures tissue architecture. Few observations have included the histologic relationships between cells.In this study we attempted to perform cytophotometric DNA analysis on intact tissue sections, thereby preserving histologic relationships, on a selected series of breast carcinomas which were proven to be bimodal or polymodal using conventional flow cytometric DNA analysis. Our objective was to explore whether distinct clonal populations are intimately admixed or whether the); are anatomically separated within the tumors. MATERIALS AND METHODSCase Selection All tumors ( N = 2 6 ) were invasive ductal carcinomas on which flow cytometric (FCM) DNA analysis had been performed prospectively (years 1987-1994, see below for FCM technique and histogram interpretation). Nineteen of these cases displayed DNA content heterogeneity, defined as presence of more than one neoplastic stemline in the DNA histogram from a representative tumor slice. DNA content heterogeneity may exhibit ...
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