Biomedical subjects

S H Barsky

Publications and source records attributed to S H Barsky.

At least 19 recordsLinked to original sources

PubMed1999

Prognostic role of p27Kip1 and apoptosis in human breast cancer.

Human breast carcinoma is biologically heterogeneous, and its clinical course may vary from an indolent slowly progressive one to a course associated with rapid progression and metastatic spread. It is important to establish prognostic factors which will define subgroups of patients with low vs high risk of recurrence so as to better define the need for additional therapy. Additional characterization of the molecular make-up of breast cancer phenotypes should provide important insights into the biology of breast cancer. In the present study, we investigated apoptosis, expression of p27Kip1 and p53 retrospectively in 181 human breast cancer specimens. In addition, their relevance to the biological behaviour of breast cancer was examined. Our studies found a significant association among high histological grade, high p53, low apoptosis and low p27. Our results also demonstrated that, in human breast cancer, low levels of p27 and apoptotic index (AI) strongly correlated with the presence of lymph node metastasis and decreased patient survival. In node-negative patients, however, p27 also had prognostic value for relapse-free and overall survival in multivariate analysis. Furthermore p27 and AI had predictive value for the benefits of chemotherapy. These latter observations should prompt prospective randomized studies designed to investigate the predictive role of p27 and AI in determining who should receive chemotherapy in node-negative patients.

Analysis of Variance↗

PubMed1998

Genistein exerts multiple suppressive effects on human breast carcinoma cells.

Dietary genistein, a natural flavone compound found in soy, has been proposed to be responsible for the low rate of breast cancer in Asian women. The cellular mechanisms of genistein's chemopreventive effects in vio have been largely unexplored. In our previous studies, we found that genistein exerted pronounced antiproliferative effects on both estrogen receptor-positive and -negative human breast carcinoma cells through G2-M arrest, induction of p21WAF1/CIP1 expression, and apoptosis. Because chemopreventive effects need not be limited to antiproliferation, we decided to examine whether genistein exerted other suppressive effects on breast carcinoma progression. Genistein inhibited invasion in vitro of MCF-7 and MDA-MB-231 cells. This inhibition was characterized by down-regulation of MMP (matrix metalloproteinase)-9 and up-regulation of tissue inhibitor of metalloproteinase-1, the former of which was transcriptionally regulated at activation protein-1 sites in the MMP-9 promoter. Genistein's in vitro effects on MMP-9 and tissue inhibitor of metalloproteinase-1 were also demonstrated in in vivo studies in nude mouse xenografts of MDA-MB-231 and MCF-7 cells. In these xenograft studies, genistein inhibited tumor growth, stimulated apoptosis, and upregulated p21WAF1/CIP1 expression. In the MDA-MB-231 xenograft, genistein also inhibited angiogenesis by decreasing vessel density and decreasing the levels of vascular endothelial growth factor and transforming growth factor-beta1. These in vitro and in vivo studies demonstrate that genistein exerts multiple suppressive effects on breast carcinoma cells, suggesting that its mechanism of chemoprevention is pleiotropic.

Animals↗

PubMed1998

Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of marijuana, cocaine, and/or tobacco.

BACKGROUND: Tobacco smoking has been observed to cause molecular alterations in bronchial epithelium that antedate the development of lung carcinoma. The rising prevalence of marijuana and cocaine use among young adults in the United States prompted us to investigate whether similar molecular and histopathologic alterations occur in habitual smokers of marijuana and/or cocaine who may or may not also smoke tobacco. METHODS: Bronchoscopy was performed in 104 healthy volunteer subjects, including 28 nonsmokers and 76 smokers of one or more of the following substances: marijuana, tobacco, and/or cocaine. Bronchial mucosa biopsy specimens and brushings were analyzed for histopathologic changes, for immunohistopathologic expression of intermediate or surrogate end-point markers that are linked to an increased risk of cancer (Ki-67 [a marker of cell proliferation], epidermal growth factor receptor, p53, Her-2/neu [also known as erbB-2 and ERBB2], globular actin, and abnormal DNA ploidy). Reported P values are two-sided. RESULTS: Smokers of any one substance or of two or more substances exhibited more alterations than nonsmokers in five to nine of the 10 histopathologic parameters investigated (all P < .05), and they exhibited more molecular abnormalities than nonsmokers. Differences between smokers and nonsmokers were statistically significant (all P < or = .01) for Ki-67, epidermal growth factor receptor, globular actin, and DNA ploidy. There was general agreement between the presence of molecular abnormalities and histopathologic alterations; however, when disagreement occurred, the molecular abnormalities (e.g., Ki-67 and epidermal growth factor receptor) were more frequently altered (all P < or = .01). CONCLUSIONS: These findings suggest that smoking marijuana and/or cocaine, like tobacco smoking, exerts field cancerization effects on bronchial epithelium, which may place smokers of these substances at increased risk for the subsequent development of lung cancer.

Actins↗

PubMed1998

The human myoepithelial cell exerts antiproliferative effects on breast carcinoma cells characterized by p21WAF1/CIP1 induction, G2/M arrest, and apoptosis.

Ductal carcinoma in situ of the breast (DCIS) is surrounded by a layer of myoepithelial cells. Our previous studies have suggested that these myoepithelial cells exert paracrine tumor-suppressive effects on invasion of breast carcinoma cells. Conditioned medium (CM), concentrated 10-100x of HMS-1, HMS-3, and HMS-4, human myoepithelial cell lines, block Matrigel invasion of a series of carcinoma cell lines. Immunoprecipitation of maspin, a recently described serpin, from these CM abolishes this anti-invasive effect. Both CM and maspin-immunoprecipitated CM, however, exert equal antiproliferative effects on a series of ER+ and ER- cell lines including MCF-7, T47D, MDA-MB-231, and MDA-MB-468. These antiproliferative effects are characterized by induction of a G2/M arrest, a twofold increase in p21(WAF1/CIP1) transcription and expression, and a threefold increase in apoptosis in the breast carcinoma lines examined. The antiproliferative effects mediated by myoepithelial cell CM do not manifest themselves in an autocrine manner, are not mediated by TGF-beta1, nor involve ER- or p53-dependent pathways. Neither the antiproliferative nor the anti-invasive effects of myoepithelial cell CM is observed with nonmyoepithelial cell CM. The in vitro observations of our present study may have relevance in explaining the increased degree of apoptosis exhibited by DCIS cells in vivo. Our findings illustrate another way myoepithelial cells function as natural paracrine tumor suppressors.

Apoptosis↗

PubMed1998

Minimally invasive breast carcinoma staging using lymphatic mapping with radiolabeled dextran.

BACKGROUND: The sentinel lymph node is defined as the first lymph node to receive drainage from a primary tumor. Based on this concept, the authors set out to evaluate whether the status of the sentinel lymph node can accurately predict whether breast tumor cells have metastasized to the axillary lymphatic basin. METHODS: Radiolabeled dextran was injected into the site of the breast tumor. In the operating room, a portable gamma detector probe was used to identify the exact location of the sentinel lymph node(s). After identifying and excising the radioactive sentinel lymph node specimens, a routine axillary lymph node dissection was performed. All lymph nodes were then subjected to hematoxylin and eosin (H & E) staining, and the sentinel lymph nodes were subjected to additional cytokeratin immunohistochemistry. RESULTS: Of the 41 patients who participated in the study, 18 had tumor metastasis to their axillary lymph nodes. In all 18 of these cases, the sentinel lymph node(s) contained cancer detected by either H & E staining or cytokeratin immunohistochemistry. CONCLUSIONS: The status of the sentinel lymph node(s) appears to predict accurately whether breast tumor cells have metastasized to the axillary lymphatic basin. This new, minimally invasive technique for staging breast carcinoma should be further validated in a large, multi-institutional clinical trial.

Breast Neoplasms↗

PubMed1998

Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by P21WAF1/CIP1 induction, G2/M arrest, and apoptosis.

Genistein has been proposed to be responsible for lowering the rate of breast cancer in Asian women but the mechanism for this chemopreventive effect in vivo is unknown. In this study, we present in vitro evidence that genistein inhibits cell proliferation similarly in ER-positive and ER-negative human breast carcinoma cell lines. This inhibition is associated with specific G2/M arrest and induction of p21WAF1/CIP1 expression. Genistein results in a five-to six-fold increase in p21WAF1/CIP1 mRNA levels and a three- to four-fold increase in protein levels, only a 1.5-fold increase in p21WAF1/CIP1 transcription but a three- to six-fold increase in p21WAF1/CIP1 mRNA stability. The increase in p21WAF1/CIP1 is followed by increased apoptosis. The similar effects of genistein on a number of breast carcinoma cell lines with different ER and p53 status suggest that the actions of genistein reported here are mediated through ER and p53 independent mechanisms. The chemopreventive effects of genistein in vivo could be mediated along an identical or similar anti-proliferative pathway.

Antineoplastic Agents↗

PubMed1998

Humatrix, a novel myoepithelial matrical gel with unique biochemical and biological properties.

Myoepithelial cells in situ and in vitro exert important paracrine effects on carcinoma cells which are mediated by high expression of extracellular matrix molecules, proteinase inhibitors and angiogenic inhibitors. Myoepithelial xenografts (human matrix secreting (HMS)-X, HMS-3X and HMS-4X) established from benign human salivary gland and breast myoepithelial tumors accumulate an abundant extracellular matrix which can be extracted with 6 M urea and 2 M guanidinium hydrochloride to form a gel at 25-37 degrees C. This gel, termed Humatrix, exhibits different biochemical and biological properties than the conventional non-human matrical gels in existence, i.e. Matrigel and Vitrogen 100. Whereas Matrigel consists mainly of basement membrane molecules, e.g. laminin, type IV collagen and heparan sulfate proteoglycan, and Vitrogen 100 consists mainly of non-basement membrane molecules, e.g. type I and type III collagen, Humatrix contains significant amounts of both basement membrane and non-basement membrane molecules, including large amounts of chondroitin sulfate proteoglycan. Like Matrigel, Humatrix contains bound growth factors, including epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I); unlike Matrigel, which contains predominantly significant quantities of bound proteinases, including tissue-type plasminogen activator (tPA), matrix metalloproteinase (MMP)-2 and MMP-9, and angiogenic factors, including basic fibroblast growth factor (bFGF) and transforming growth factor (TGF)-beta, Humatrix contains predominantly bound proteinase inhibitors such as protease nexin II (PN-II) and alpha1-antitrypsin and angiogenic inhibitors such as thrombospondin-1. Humatrix selectively stimulates the growth and tumorigenicity of human myoepithelial cell lines but inhibits invasion, angiogenesis and metastasis of other non-myoepithelial malignant cell lines. Because of its myoepithelial origin Humatrix represents a more natural source of extracellular matrix molecules and bound factors that carcinoma cells encounter in vivo.

Animals↗

PubMed1998

Altered mucin expression is a field change that accompanies mucinous (colloid) breast carcinoma histogenesis.

Mucinous carcinomas of the breast, so-called colloid carcinomas, exhibit better prognoses than their nonmucinous breast counterparts. This biological difference exhibited by mucinous breast carcinomas prompted us to examine the relationship of mucin expression to colloid carcinoma histogenesis. We studied 50 colloid carcinomas, 50 noncolloid cancers, and 50 normal breasts by hematoxylin-eosin (H&E) and Alcian blue staining, mucin immunohistochemistry, in situ hybridization with a battery of MUC riboprobes, and ancillary digital image analysis. We observed luminal mucin in normal ducts in 80% of colloid carcinomas compared with 10% of noncolloid carcinomas and 6% of normal breasts (P < .01). In the cases of colloid carcinoma that showed mucin-filled ducts, luminal mucin was observed in 40% of the normal ducts and acini, 40% to 75% of the ducts involved by hyperplasia, atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), respectively, and in 50% of the co-incidental areas of cysts (mucoceles), adenosis, fibroadenoma, and intraductal papilloma (P < .01). Immunohistochemistry showed that colloid carcinomas showed strong MUC2 cytoplasmic immunoreactivity and decreased MUC1 immunoreactivity compared with noncolloid carcinomas. In situ hybridization studies indicated fivefold increased MUC2 signals and twofold increased MUC5 signals within adjacent and remote normal epithelium in only the colloid carcinoma cases (P < .01; P < .05). In these cases of colloid carcinoma, these increased MUC2 and MUC5 signals were also observed in areas of hyperplasia, ADH, DCIS, and invasive carcinoma. In contrast, the noncolloid carcinomas showed fivefold increased MUC1 signals but no increases in MUC2 or MUC5. In mixed colloid/noncolloid carcinomas, the colloid areas had identical mucin expression patterns as the pure colloid carcinomas, but there was a loss of MUC2 and MUC5 expression and a gain of MUC1 expression in the noncolloid areas that was therefore identical to the pattern observed in pure noncolloid carcinoma. In this study, we conclude that the altered expression of mucin so characteristic of colloid carcinoma is also a field change present in adjacent and remote normal breast epithelium.

Adenocarcinoma, Mucinous↗

PubMed1998

Airway inflammation in young marijuana and tobacco smokers.

Forty healthy young subjects, ages 20 to 49 yr, underwent videobronchoscopy, mucosal biopsy, and bronchial lavage to evaluate the airway inflammation produced by habitual smoking of marijuana and/or tobacco. Videotapes were graded in a blinded manner for central airway erythema, edema, and airway secretions using a modified visual bronchitis index. The bronchitis index scores were significantly higher in marijuana smokers (MS), tobacco smokers (TS), and in combined marijuana/tobacco smokers (MTS), than in nonsmokers (NS). As a pathologic correlate, mucosal biopsies were evaluated for the presence of vascular hyperplasia, submucosal edema, inflammatory cell infiltrates, and goblet cell hyperplasia. Biopsies were positive for two of these criteria in 97% of all smokers and for three criteria in 72%. By contrast, none of the biopsies from NS exhibited greater than one positive finding. Finally, as a measure of distal airway inflammation, neutrophil counts and interleukin-8 (IL-8) concentrations were determined in bronchial lavage fluid. The percentage of neutrophils correlated with IL-8 levels and exceeded 20% in 0 of 10 NS, 1 of 9 MS, 2 of 9 TS, and 5 of 10 MTS. We conclude that regular smoking of marijuana by young adults is associated with significant airway inflammation that is similar in frequency, type, and magnitude to that observed in the lungs of tobacco smokers.

Adult↗

PubMed1997

Evidence of a dominant transcriptional pathway which regulates an undifferentiated and complete metastatic phenotype.

The highly metastatic amelanotic C8161 human melanoma line was found to exhibit complete dominance of its undifferentiated and metastatic phenotype in multiple somatic cell hybridization studies designed to bypass the presence of potential tumor suppressor genes. In a three armed approach involving somatic cell fusions of C8161 with recipient lines of greater differentiation, different lineage, and different tumorigenicity status, the metastatic and undifferentiated phenotype of C8161 was promiscuously dominant. In somatic cell hybrids produced between the C8161 and a group of non-metastatic human melanoma lines which exhibited melanocyte differentiation markers including S100, HMB-45, NKI/C3, and melanin, the fusions were uniformly metastatic and undifferentiated. In somatic cell hybrids of C8161 and MCF-7 the fusions exhibited an estrogen independent and unresponsive, estrogen receptor (ER) negative, and highly metastatic phenotype. In fusions between C8161 and HMS-1, an immortalized 'benign' human myoepithelial line which produced an abundant extracellular matrix (ECM) and high levels of protease and angiogenic inhibitors including maspin, tissue inhibitor of metalloproteinase-1 (TIMP-1), alpha1-antitrypsin (alpha1-AT), protease nexin II (PN-II), thrombospondin-1 and soluble basic fibroblast growth factor (bFGF) receptors, the hybrids showed complete absence of matrix, absent maspin expression, markedly decreased protease inhibitor and angiogenic inhibitor production, high levels of proteases and angiogenic factors, and a highly metastatic phenotype. In our somatic cell fusions, the human-human hybrids represented true and complete fusions and not hybrid clones selected for by loss of dominant-acting growth suppressor genes. This finding was supported by detailed comparative genomic hybridization (CGH) studies, Q-banding karyotype analysis, and autofusions of representative clones. The purposeful creation of inherently unstable human-murine fusions between C8161 and B16-F1 where loss of putative suppressor loci would be expected, resulted in fusions exhibiting decreased growth and non-metastatic behavior with progressive chromosomal loss. Neither p53, nm23, DNA methyltransferase, activated ras, fibroblast growth factor-4 (FGF-4), or epidermal growth factor receptor (EGFR) mediated the acquisition of the metastatic or undifferentiated phenotype within the C8161-human fusions. These studies are the first studies ever to successfully transfer the complete metastatic phenotype by somatic cell fusion and support the presence of a new high level regulatory pathway(s) involving dominant trans-acting factors which act pleiotropically to regulate an undifferentiated and highly metastatic phenotype.

Animals↗

PubMed1997

'Revertant' DCIS in human axillary breast carcinoma metastases.

Recent experimental evidence obtained in Scid mice has suggested that the metastatic process is in large part epigenetically regulated and undergoes partial reversion once the metastatic process is completed: the metastatic colonies become more engaged in the process of growing in situ than actively metastasizing. Based on this experimental evidence, examples were sought of metastatic human cancers where similar reversion to an in situ growth state was occurring. Review of 200 cases of metastatic human breast cancer revealed a 21 per cent incidence of reversion to a ductal carcinoma in situ (DCIS) growth pattern within axillary nodal metastases. The revertant DCIS areas were characterized by an intact and circumferential basement membrane, as demonstrated by extracellular laminin and type IV collagen immunoreactivity. These revertant DCIS areas could be distinguished from primary DCIS, however, by the absence of surrounding myoepithelial cells in the former, identified in the latter by their positive maspin, S-100, and smooth muscle actin immunoreactivity. The pattern of revertant DCIS, poorly differentiated (comedo) (13 per cent), intermediate (non-comedo) (6 per cent), or well-differentiated (non-comedo) (2%), exhibited complete 100 per cent concordance with the primary DCIS pattern. The concordance of histological patterns held true for even the subtypes of DCIS determined by architectural pattern, such as the micropapillary or cribriform subtypes. Nuclear size by digital image analysis and Her-2/neu, p53, and Ki-67 status in the revertant DCIS also exhibited complete concordance with the primary DCIS counterparts. Cases exhibiting a revertant DCIS pattern tended to be ER-negative/EGFR-positive and exhibited significant nodal involvement (mean number, 9; mean area, 90 per cent) compared with cases lacking a revertant pattern (mean number, 4; mean area, 15 per cent) (P < 0.01) These findings suggest that reversion of the metastatic phenotype may also be occurring within autochthonous human metastasis.

Axilla↗

PubMed1997

The myoepithelial defense: a host defense against cancer.

The behavior of human tumors depends not only on the nature of the tumor cells themselves but also on the modifying effects of various normal host cells such as fibroblasts and endothelial cells. One cell type, however--the myoepithelial cell--has not been studied scientifically. Myoepithelial cells normally surround ducts and acini of glandular organs such as the breast and salivary glands and contribute to the synthesis of a surrounding basement membrane. This relationship suggests that myoepithelial cells may exert paracrine effects on glandular epithelium and also regulate the progression of ductal carcinoma in situ (DCIS) to invasive carcinoma. Myoepithelial tumors, in turn, tend to be benign or low-grade neoplasms that exhibit the rare property of accumulating rather than degrading extracellular matrix material. To better understand the nature of myoepithelial tumors, as well as the possible role of normal myoepithelial host cells in cancer, we have established immortal cell lines and a number of transplantable xenografts from various human myoepithelial tumors of the salivary gland and breast. The cell lines exhibit a normal myoepithelial phenotype and the xenografts continue to accumulate an abundant extracellular matrix. Further ultrastructural, immunocytochemical, molecular, and biochemical studies reveal that myoepithelial cells secrete relatively low levels of matrix-degrading proteinases but relatively high levels of maspin and various other anti-invasive proteinase inhibitors, that some of these inhibitors accumulate within the myoepithelial matrix, and that myoepithelial cells can induce epithelial morphogenesis (spheroid formation) and inhibit tumor-cell invasion in vitro. Myoepithelial cells, which surround normal breast ducts and DCIS, have also been found to selectively express maspin and certain proteinase inhibitors in situ. These inherent myoepithelial properties are likely to contribute to the low-grade nature of myoepithelial neoplasms and advance our hypothesis that host myoepithelial cells regulate the progression of in situ to invasive carcinoma by providing an important host defense against cancer invasion.

Animals↗

PubMed1997

Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and/or tobacco.

BACKGROUND: Marijuana and alkaloidal cocaine ("crack") are the two most commonly smoked substances in the United States after tobacco. While regular tobacco smoking has been found to be associated with extensive microscopic alterations in bronchial mucosa, little information is available concerning the effect of crack cocaine and marijuana on tracheobronchial histopathology. STUDY OBJECTIVE: To determine the relative impact of smoked substances (cocaine, marijuana, and tobacco) alone and in combination on the histopathology of the tracheobronchial mucosa and to assess whether the effects of habitual smoking of two or more substances (cocaine, marijuana, and/or tobacco) are additive. DESIGN: Observational cohort study. SUBJECTS: Fifty-three nonsmoking control subjects (NS), 14 current, habitual smokers of crack cocaine only (CS), 40 current, regular smokers of marijuana only (MS), 31 regular smokers of tobacco only (TS), 16 current smokers of both cocaine and marijuana (CMS), 12 current smokers of both cocaine and tobacco (CTS), 44 current smokers of both marijuana and tobacco (MTS), and 31 current smokers of cocaine, marijuana, and tobacco (CMTS). METHODS: After preliminary screening evaluation, including a detailed respiratory and general health questionnaire and routine pulmonary function studies, subjects underwent fiberoptic bronchoscopy with endobronchial biopsies of the mucosa of the primary carina and randomly selected secondary or tertiary carinae. Biopsy specimens were processed for light microscopy, stained with hematoxylin-eosin or periodic acid-Schiff, and examined to assess epithelial, basement membrane, and submucosal alterations by one or two pathologists who were masked to the smoking status of the subject. RESULTS: Smokers of cocaine, marijuana, or tobacco alone all exhibited more frequent abnormalities than NS in 10 (CS) or all 11 (MS and TS) of the histopathologic features assessed. For most features, MS and TS showed significantly more frequent alterations than NS (p < or = 0.02), while CS showed significantly more frequent abnormalities than NS in only three features (p<0.05) and nearly significant differences from NS in two additional features (p < or = 0.09). Alterations were noted most frequently in CTS (six features) and MTS (three features), while abnormalities were relatively infrequent in CMS. For 10 features, MTS had more frequent alterations than MS and TS. With a single exception, CMTS did not show more frequent alterations than CTS or MTS. CONCLUSION: Marijuana and tobacco smoking each produces significant bronchial mucosal histopathology and the effects of marijuana and tobacco appear additive. Cocaine appears to lead to fewer significant bronchial mucosal alterations than marijuana or tobacco when smoked alone and does not add to the changes associated with marijuana. When smoked together with tobacco, however, cocaine appears to augment the bronchial injury caused by tobacco smoking.

Adult↗

PubMed1997

Ectopic G-CSF expression in human melanoma lines marks a trans-dominant pathway of tumor progression.

Using a human melanoma/Scid xenograft model with the C8161, M24-met, LD-1 and other human melanoma lines to investigate spontaneous metastasis, we made the observation of marked splenomegaly (up to five times normal weight and size) in only those xenografts exhibiting high degrees of spontaneous metastasis. Evaluation of this revealed the cause to be massive myelopoiesis due to ectopic granulocyte/ colony-stimulating factor (G-CSF) production by the melanoma cells. Because of these observations linking G-CSF expression with metastasis of human melanoma, we decided to investigate the mechanism of this ectopic production. No gross amplification or rearrangement of the G-CSF gene could be detected as the basis for the increased transcriptional activity in any of these lines. Human-human somatic cell hybridization studies carried out between the metastatic C8161 and several different nonmetastatic non-G-CSF-expressing lines revealed, in addition to metastatic dominance, 3- to 10-fold enhancement of G-CSF transcription and expression in the fusions compared with C8161 itself. The suggestion of a trans-dominant mechanism was further supported by transfection studies with a human G-CSF promoter-CAT-reporter construct, which revealed 3- to 5-fold increased reporter activity in only those melanoma lines and hybrids expressing G-CSF. Furthermore, no obvious autocrine or paracrine effects of this ectopic G-CSF expression on the melanoma lines' growth or metastasis were apparent, as all of the G-CSF-expressing lines lacked the G-CSF receptor and injections of purified recombinant G-CSF exerted no stimulatory effects on their tumorigenicity, latency, growth, or metastasis in Scid mice. Thus, we advance the hypothesis that G-CSF expression is serving as a marker of a more generalized trans-dominant pathway linked to tumor progression and metastasis. This hypothesis has direct relevance to many human cancers where ectopic hormone or growth factor production occurs with no obvious autocrine or paracrine benefit to the tumor.

Animals↗

PubMed1997

Vascular expression of E-selectin is increased in estrogen-receptor-negative breast cancer: a role for tumor-cell-secreted interleukin-1 alpha.

Angiogenesis plays an important role in breast cancer growth and metastasis. Multiple adhesion molecules have been shown to perform critical functions in the process of angiogenesis. In this study, we analyzed 15 benign and 22 malignant estrogen-receptor-negative and estrogen-receptor-positive breast specimens for the presence of the endothelial cell adhesion molecules E-selectin and P-selectin. We found that E-selectin's expression was increased in the malignant breast tumors compared with their benign counterparts (23.86% of blood vessels versus 2.47%; P = 0.0005). Furthermore, E-selectin staining was found to be significantly increased in the estrogen-receptor-negative carcinomas compared with the estrogen-receptor-positive ones (P = 0.005). In vitro findings strongly correlated with the in vivo findings and showed a higher degree of E-selectin induction in endothelial cells exposed to conditioned media from estrogen-receptor-negative breast cancer cell lines than from estrogen-receptor-positive ones. The degree of E-selectin induction correlated with the amount of interleukin-1 alpha in the tumor-conditioned media. Neutralizing antibodies to interleukin-1 alpha significantly inhibited the E-selectin expression in endothelial cells exposed to tumor-conditioned media. The results indicate that the endothelial E-selectin expression during angiogenesis is related to breast carcinoma progression in vivo and that this component of angiogenesis may be due directly to tumor-cell-secreted interleukin-1 alpha.

Breast Neoplasms↗

PubMed1997

The human myoepithelial cell is a natural tumor suppressor.

Myoepithelial cells, which surround ducts and acini of glandular organs, form a natural border separating proliferating epithelial cells from basement membrane and underlying stroma. Myoepithelial cells in situ and in vitro constitutively express high amounts of proteinase inhibitors that include tissue inhibitor of metalloproteinase 1, protease nexin-II, alpha-1 antitrypsin, and maspin. Human myoepithelial xenografts (HMS-X, HMS-3X, and HMS-4X), which our laboratory has established, accumulate an abundant extracellular matrix containing sequestered proteinase inhibitors. Humatrix, a gel that we have derived from HMS-X, inhibits tumor cell invasion (down to 25% +/- 10% of Matrigel control; P < 0.01), and our recently established human myoepithelial cell lines, HMS-1, HMS-3, and HMS-4, inhibit tumor cell invasion in cellular invasion (down to 42% +/- 7% of control; P < 0.05) and in conditioned media assays (down to 30% +/- 8% of control; P < 0.01). The anti-invasive effects of HMS-1, HMS-3, and HMS-4 can be enhanced by phorbol 12-myristate 13-acetate (down to 2% +/- 1% of control) by a maspin-dependent mechanism and abolished by dexamethasone (up to 95% +/- 5% of control) by a maspin-independent mechanism (P < 0.01). HMS-X, HMS-3X, HMS-4X, and Humatrix inhibit tumor invasion and metastasis in severe combined immunodeficient mice (P < 0.001). The cumulative data suggest that myoepithelial cells are natural paracrine suppressors of invasion and metastasis and may specifically inhibit the progression of precancerous disease states to invasive cancer in vivo.

Animals↗

PubMed1996

An update on core needle biopsy for radiologically detected breast lesions.

BACKGROUND: Traditionally, radiologically detected lesions of the breast have been evaluated by open surgical biopsy with wire localization. Recently, core needle biopsy has been introduced as an alternative to open surgical biopsy. The authors evaluated their own results with long term follow-up after core needle biopsy and reviewed the experience of other physicians with this new technique. METHODS: Four hundred thirty-one core needle biopsies performed at UCLA were analyzed. The outcome of these cases was determined by either surgery or long term follow-up. Statistical analysis was performed to determine the accuracy of the method. RESULTS: Definitive outcome was obtained in 96% of the core needle biopsy cases, with a median follow-up time of 18 months (range, 6-38 months). The authors achieved a sensitivity of 99% and a specificity of 100%. The false-negative rate was 1.7%. There were no complications in this series. CONCLUSIONS: Core needle biopsy is a highly accurate and safe method for the diagnosis of radiologically detected lesions of the breast.

Biopsy, Needle↗

PubMed1996

Breast-duct endoscopy to study stages of cancerous breast disease.

BACKGROUND: In breast-cancer research, we lack reproducible non-invasive access to breast tissue. Breast cancer is thought to start in the lining of the milk duct or lobule. We have had no direct access to this area other than in tissue removed surgically or by fine-needle aspiration. Our objective was to explore an intraductal approach to studying breast cancer and precancerous changes by duct cannulation and endoscopy. METHODS: In this pilot study, women in a university hospital were asked to participate. Nine patients with previously diagnosed ductal carcinoma-in-situ (DCIS) or invasive breast cancer who were about to undergo mastectomy under general anaesthesia agreed. After the patient was asleep but before the operation, we spent 15 minutes cannulating their ducts, obtaining washings, and attempting endoscopy. The ducts that had been cannulated were marked by instillation of dye or other materials, the nipple was sutured shut, and the mastectomy proceeded as planned. The mastectomy specimen underwent extensive histopathological examination. FINDINGS: We were successful in intraductal cannulation and endoscopy in seven of the nine patients. In five of the nine, we obtained epithelial cells in the washings. In one the cells were consistent with proliferative disease, in three there was atypical epithelium, and in one there was frank DCIS. With several different contrast materials injected into separate duct orifices, DCIS was confined to a single duct system. INTERPRETATION: We found that the intraductal approach is feasible for the study of the early changes of breast cancer Technical difficulties include identification of the breast duct orifices, determining the distensibility of the duct, and developing a reliable technique to obtain washings.

Anesthesia, General↗