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PubMed2026

Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.

UNLABELLED: Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in patients with recurrent high-grade glioma treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAM), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the TME. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2-M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62, and autophagosome accumulation and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and damage-associated molecular patterns (DAMP), such as IL1β, HMGB1, and extracellular ATP. Coculturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and proinflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the antitumor therapeutic efficacy of OD-0J1. SIGNIFICANCE: Leveraging JAG1 antagonism in the context of oncolytic virotherapy rewires macrophage polarization within the tumor microenvironment, which has wide implications for sensitizing tumors to antibodies, senolytic agents, and BiTE therapies.

Humans↗
PubMed2000

Increased plasma levels of mature adrenomedullin in chronic glomerulonephritis.

Adrenomedullin (AM) is a potent vasodilative and natriuretic peptide that is processed from its precursor as the intermediate form, AM-glycine-COOH (iAM). Subsequently, iAM is converted to the biologically active mature form, AM(1-52)-CONH(2) (mAM), by enzymatic amidation. Using immunoradiometric assays that recognize total AM (tAM) and only mAM, we determined the plasma and urinary levels of mAM and iAM in patients with chronic glomerulonephritis (CGN). The plasma mAM concentration was significantly higher in the patients than in the controls (1.8 +/- 0.1 vs. 1.3 +/- 0.1 fmol/ml, p < 0.01), whereas the plasma iAM concentration of the CGN patients did not significantly differ from that of the controls (9.4 +/- 0.5 vs. 8.9 +/- 0.5 fmol/ml). Levels of urinary mAM excretion in the patients did not statistically differ from those of the controls (1. 6 +/- 0.4 vs. 2.0 +/- 0.3 fmol/mg creatinine), whereas urinary iAM excretion was significantly lower in the CGN patients (3.7 +/- 0.7 vs. 5.6 +/- 0.8 fmol/mg creatinine, p < 0.05). Urinary excretion levels of mAM significantly correlated with those of sodium (r = 0. 47, p < 0.05), whereas those of iAM did not. In conclusion, the plasma ratio of mAM to iAM is augmented in CGN patients, and mAM appears to be involved in the regulation of sodium. Therefore, determination of the mAM in addition to the tAM concentration is essential in CGN patients.

Adolescent↗
PubMed2003

Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer.

Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 +/- 17% (p = 0.33) and 21 +/- 11% (p = 0.060), respectively. Multivariate analysis using Cox's proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 +/- 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 +/- 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I - IIIA breast cancer for the prolongation of the recurrence-free survival period.

Adult↗
PubMed2006

Co-opting macrophage traits in cancer progression: a consequence of tumor cell fusion?

Tumor-associated macrophages (TAMs) play multiple roles in tumor initiation and progression. Tumors frequently appear in areas of chronic inflammation. This is likely aided by the mutagenic actions of macrophages. Tumor growth and progression is supported by macrophage-induced neoangiogenesis and stroma production, and macrophages produce tumor-stimulating growth factors. In most cancers a high density of TAMs predicts poor outcome. But not only do cancer cells depend upon macrophages for growth and invasion, they also co-opt macrophage traits. These include a wide diversity of molecules and pathways regulating adhesion, matrix alterations, neoangiogenesis, motility, chemotaxis, immune signaling pathways and even multidrug resistance proteins. Evidence is presented that these traits could be generated through macrophage-tumor cell fusion. Fusion has been reported in numerous animal tumor models and was recently documented in 2 human cases. Fusion could also account for the high degree of aneuploidy and plasticity in cancer, and for immune evasion. One common trait of myeloid-tumor fusion is the high expression of Beta1,6-branched N-glycans, used by macrophages in systemic migration. Beta1,6-branched oligosaccharides have long been associated with metastasis in animal models and were recently found to be common in a wide diversity of human cancers. We suggest that Beta1,6-branched oligosaccharides in human cancer may reflect widespread tumor cell fusion. Viewing the cancer cell as a myeloid hybrid provides new approaches towards understanding and treating this complex disease.

Bone Marrow Neoplasms↗
PubMedDate not supplied

Telephone-Assessed Mental State.

In 30 patients with Alzheimer's disease (AD), we compared performance on a brief Telephone-Assessed Mental State (TAMS) examination with performance on standard cognitive instruments administered face to face. TAMS scores correlated strongly with scores on both the Mini Mental State Examination (rho = 0.81) and the Alzheimer's Disease Assessment Scale (rho = -0.80).

Aged↗
PubMed1997

Additional chromosome abnormalities in transient abnormal myelopoiesis in Down's syndrome patients.

We report a case of transient abnormal myelopoiesis (TAM) with Down's syndrome. As the blast cells had additional chromosome abnormalities (50,XY,+12,+14,+21 x 2), a possibility of acute leukemia was considered from a cytogenetic point of view. But the abnormal clone gradually disappeared without antileukemic therapies. Viewing it together with previous reports of TAM with additional chromosome abnormalities in Down's syndrome babies, its presence does not immediately indicate an aggressive clinical course as in acute leukemia and spontaneous complete hematological remission may be achieved. Thus, a careful follow-up should precede cytogenetic findings helping to determine the therapeutic intervention.

Adult↗
PubMed1988

Different expression of procoagulant activity in macrophages associated with experimental and human tumors.

Mononuclear phagocytes, an integral part of the lymphoreticular infiltrate of human and experimental tumors, might contribute to fibrin deposition within malignant tissues through the production of procoagulant activity (PCA). Recent studies in different types of experimental tumors and in some cancer patients indicate that the functional status in terms of PCA of mononuclear phagocytes at 'peripheral' sites is not the same as that of macrophages at the tumor site (tumor-associated macrophages, TAM). Peripheral blood monocytes and/or peritoneal macrophages from V2-carcinoma-bearing rabbits and from mice bearing different types of tumors, like cells from normal animals, have low levels of basal PCA and are able to respond with a marked increase in PCA to in vitro stimulation. Likewise, in patients with primary lung cancer, pulmonary alveolar macrophages (PAM) obtained from the contralateral side of the neoplasm and blood monocytes behave essentially as cells from normal individuals. In contrast, profound changes in PCA have been found in TAM. In some experimental tumors and in a number of the patients, macrophages taken at the tumor site express high levels of basal PCA, which most probably reflect in vivo activation. Local activation of macrophages for PCA production might contribute to fibrin deposition at the tumor site. In the other experimental tumors studied and in the remaining patients, not only have macrophages low basal PCA but they also fail to respond to various stimulants in vitro. Although the mechanisms underlying these changes and their pathophysiological significance remain to be established, it is apparent that neoplastic growth may modulate the expression of macrophage PCA at the tumor site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of 17 beta-estradiol, progesterone and tamoxifen on in vitro proliferation of human pituitary adenomas: correlation with specific cellular receptors.

Six human pituitary adenoma cultures, characterized for estrogen and progesterone (Pg) receptors, were treated with 17 beta-estradiol (17 beta-E2), Pg and tamoxifen (TAM) at different concentrations, alone and in combination, for 2, 4 and 8 days. Cell proliferation data showed in most cases a stimulating effect of 17 beta-E2 and an inhibitory effect of Pg on cell growth, which appeared to be correlated with specific receptor expression, but independent of pituitary cell hormone content. A marked inhibitory effect of TAM on cell proliferation was present in all cases, but, on the contrary, was independent of estrogen receptor expression.

Adenoma↗
PubMed1995

Normal thoracoabdominal motions. Influence of sex, age, posture, and breath size.

The purpose of this study was to assess normal values of thoracoabdominal motions (TAM) during spontaneous breathing and vital capacity (VC) maneuvers in relation to sex, age, and body position. For this, 120 healthy subjects from 10 to > 60 yr old were studied using the respiratory inductive plethysmograph (Respitrace). The volume-motion coefficients obtained during quiet breathing for the rib cage (RC) were almost twice those for the abdomen (ABD) and were not influenced by sex or age and also not by posture, except for the increased ABD coefficients in the supine posture (p < 0.05). Under most conditions RC motion predominated over ABD motion, except quiet breathing in the supine position. Sex-related differences in TAM were not found during quiet breathing, yet during VC maneuvers the women were slightly more RC breathing (p < 0.01). Age-related differences were also only significant during VC maneuvers: men of more than 50 yr old especially became less RC breathing. Posture had a very significant effect (p < 0.001) during quiet breathing as well as during VC maneuvers: the RC predominance was greatest in the standing posture and least in the supine posture. During VC maneuvers the subjects became more RC breathers than during quiet breathing (p < 0.001). The X-Y coordinates of RC motion (on the Y axis) versus ABD motion (on the X axis) showed under all conditions a counterclockwise looping during the breathing cycle: the looping was elliptic during quiet breathing but was more irregular and variable during VC maneuvers, and this also depended on body position.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMedDate not supplied

Changes in receptor status after treatment with tamoxifen in endometrial cancer.

Estrogen (ER) and progesterone receptor (PgR) status was determined in 41 women with operable endometrial cancer before and after administration of tamoxifen (TAM). The first sample was obtained by hysteroscopy to ensure a precise biopsy of neoplastic tissue; the second was done on the surgical specimen. PgR content was significantly increased after TAM treatment and this data was compared with the degree of tumor differentiation.

Adenocarcinoma↗
PubMed2006

AIB1 gene amplification and the instability of polyQ encoding sequence in breast cancer cell lines.

BACKGROUND: The poly Q polymorphism in AIB1 (amplified in breast cancer) gene is usually assessed by fragment length analysis which does not reveal the actual sequence variation. The purpose of this study is to investigate the sequence variation of poly Q encoding region in breast cancer cell lines at single molecule level, and to determine if the sequence variation is related to AIB1 gene amplification. METHODS: The polymorphic poly Q encoding region of AIB1 gene was investigated at the single molecule level by PCR cloning/sequencing. The amplification of AIB1 gene in various breast cancer cell lines were studied by real-time quantitative PCR. RESULTS: Significant amplifications (5-23 folds) of AIB1 gene were found in 2 out of 9 (22%) ER positive cell lines (in BT-474 and MCF-7 but not in BT-20, ZR-75-1, T47D, BT483, MDA-MB-361, MDA-MB-468 and MDA-MB-330). The AIB1 gene was not amplified in any of the ER negative cell lines. Different passages of MCF-7 cell lines and their derivatives maintained the feature of AIB1 amplification. When the cells were selected for hormone independence (LCC1) and resistance to 4-hydroxy tamoxifen (4-OH TAM) (LCC2 and R27), ICI 182,780 (LCC9) or 4-OH TAM, KEO and LY 117018 (LY-2), AIB1 copy number decreased but still remained highly amplified. Sequencing analysis of poly Q encoding region of AIB1 gene did not reveal specific patterns that could be correlated with AIB1 gene amplification. However, about 72% of the breast cancer cell lines had at least one under represented (<20%) extra poly Q encoding sequence patterns that were derived from the original allele, presumably due to somatic instability. Although all MCF-7 cells and their variants had the same predominant poly Q encoding sequence pattern of (CAG)3CAA(CAG)9(CAACAG)3(CAACAGCAG)2CAA of the original cell line, a number of altered poly Q encoding sequences were found in the derivatives of MCF-7 cell lines. CONCLUSION: These data suggest that poly Q encoding region of AIB1 gene is somatic unstable in breast cancer cell lines. The instability and the sequence characteristics, however, do not appear to be associated with the level of the gene amplification.

Acetyltransferases↗
PubMed2026

FZD5 drives macrophage-mediated immunomodulation and predicts prognosis in glioma: evidence from single-cell sequencing.

BACKGROUND: Gliomas are highly malignant brain tumors characterized by an immunosuppressive microenvironment, which limits therapeutic efficacy and contributes to poor clinical outcomes. The WNT/&#x3b2;-catenin signaling pathway is critically involved in tumor progression, and FZD5, a key receptor within this pathway, may participate in immune regulation. However, its specific role and underlying mechanisms in glioma remain unclear. METHODS: RNA-seq and microarray datasets from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA), together with single-cell RNA sequencing (scRNA-seq) datasets from GEO, were comprehensively analyzed. The Seurat package was used to identify macrophage-related clusters and mitophagy-associated pathways. Cox and LASSO regression analyses, along with a prognostic nomogram, were applied to evaluate the prognostic significance of FZD5. Immune infiltration, functional enrichment, and immunotherapy response analyses were conducted, followed by validation using spatial transcriptomics, immunohistochemistry, and in vitro assays. RESULTS: In bulk glioma transcriptomes, FZD5 emerged as an independent predictor of poor prognosis. Crucially, single-cell and spatial analyses revealed that the biologically significant FZD5 signal originated predominantly within tumor-associated macrophages (TAMs), where it colocalized with the M2 marker CD163. Consistently, elevated FZD5 levels correlated with increased myeloid infiltration and an immunosuppressive tumor microenvironment. Functionally, macrophage-expressed FZD5 was associated with mitophagy-related programs and promoted an M2-skewed phenotype, thereby enhancing glioma cell proliferation, migration, and invasion via macrophage-glioma crosstalk. CONCLUSION: FZD5 is a TAM-enriched marker in glioma tissues and a potential regulator of macrophage-associated immunosuppressive programs, supporting its utility as a prognostic biomarker and a candidate target for microenvironment-oriented interventions in glioma.

Humans↗
PubMed2006

Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver.

Tamoxifen can induce hepatic steatosis in women. In this study, we wanted to elucidate the mechanism behind the tamoxifen-induced accumulation of triacylglycerol in liver in female rats, and we hoped to prevent this development by combination treatment with the modified fatty acid tetradecylthioacetic acid (TTA). The increased hepatic triacylglycerol level after tamoxifen treatment was accompanied by decreased acetyl-coenzyme A carboxylase (ACC) and FAS activities, increased glycerol-3-phosphate acyltransferase (GPAT) activity, and a tendency to increased diacylglycerol acyltransferase (DGAT) activity. The activities and mRNA levels of enzymes involved in beta-oxidation, ketogenesis, and uptake of lipids from liver were unaffected by tamoxifen, whereas the uptake of lipoproteins was unchanged and the uptake of fatty acids was decreased. Combination treatment with tamoxifen and TTA (Tam+TTA) normalized the hepatic triacylglycerol level and increased the activities of ACC, FAS, GPAT, and DGAT compared with tamoxifen-treated rats. The activities and mRNA levels of enzymes involved in beta-oxidation, ketogenesis, and uptake of lipids were increased after Tam+TTA treatment. In conclusion, tamoxifen increased the hepatic triacylglycerol level, probably as a result of increased triacylglycerol biosynthesis combined with unchanged beta-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal beta-oxidation.

Alanine Transaminase↗
PubMed2003

Signal transduction of cerulein-induced cytokine expression and apoptosis in pancreatic acinar cells.

The signaling pathways mediating cytokine production and apoptosis in pancreatic acinar cells have not been fully understood. We investigated the signal transduction of cerulein-induced cytokine IL-6 expression and apoptosis in pancreatic acinar AR42J cells. The wild-type cells and the cells transfected with mutant genes for signaling molecules (such as transcription factor NF-kappaB and AP-1) and ras, the upstream signal for mitogen-activated protein kinase (MAPK), were used. IL-6 level was determined in the medium by enzyme-linked immunosorbent assay (ELISA). Apoptosis was determined by viable cell counts and DNA fragmentation. Wild-type cells and transfected cells with control vector (pcDNA), IkappaB mutant gene (IkappaB mt), H-ras mutant gene (Ras N17), or c-jun dominant negative gene (TAM-67) were treated with cerulein for 24 hours. As a result, cerulein induced IL-6 expression time-dependently at 10(-8) M, and apoptosis dose-dependently at 24 h in the wild-type cells. Cerulein-induced IL-6 expression (at 10(-8) M) and apoptosis (at 10(-7) M) were inhibited in the transfected cells with mutant gene (IkappaB mt, Ras N17, TAM-67) as compared to pcDNA cells and the wild-type cells. In conclusion, cerulein induces cytokine expression and apoptotic cell death, which may be regulated by NF-kappaB, AP-1, and possibly MAPK in pancreatic acinar cells.

Animals↗
PubMed1986

Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial.

In this National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial, 1,891 women with primary operable breast cancer and positive axillary nodes were randomized between Jan, 1977 and May 1980 to receive L-phenylalanine mustard (L-PAM) and 5-fluorouracil (5-FU) either with or without tamoxifen (TAM)-PFT. This report presents life table probabilities, cumulative odds ratios, and P values for disease-free survival (DFS) and survival at yearly intervals through 5 years of observation (mean time on study, 72 months). When patients were examined overall without regard for any discriminant associated with outcome, ie, age, number of positive nodes, or tumor receptor status, there was a significant prolongation of DFS (P = .002), but not survival through the fifth postoperative year. The benefit was almost entirely restricted to those greater than or equal to 50 years with greater than or equal to 4 positive nodes. In that group there was a 66% greater chance of remaining disease free if PFT was received (P less than .001), and there was also a significant survival benefit (P = .02). The advantage from PFT was found to be associated with tumor estrogen receptor (ER) and progesterone receptor (PR) as well as patient age and nodal status. Overall there was a significant improvement in DFS from PFT in those having tumors with an ER or PR level greater than or equal to 10 femtomole (fmol) (P = .01 and .009, respectively). No significant benefit in DFS or survival has been observed in patients less than or equal to 49 years old related either to nodes or tumor receptor status. Survival continues to be adversely affected by TAM in those patients (less than or equal to 49 years old), particularly when their tumors have a PR of 0 to 9 fmol (P = .007). In patients greater than or equal to 50 years old with four or more positive nodes, a significant DFS benefit persisted through the fifth year of observation in those having tumor ER or PR levels greater than 10 fmol (P less than .001 and .002). The advantage was observed in patients 50 to 59 years old as well as those 60 to 70. Women in the older decade demonstrated some advantage from PFT when their tumor ER or PR was 0 to 9 fmol. The most likely explanation for this finding is analytical error in receptor analyses.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1990

Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented protocol B-15 to compare 2 months of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide (AC) with 6 months of conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with breast cancer nonresponsive to tamoxifen (TAM, T). A second aim was to determine whether AC followed in 6 months by intravenous (IV) CMF was more effective than AC without reinduction therapy. Through 3 years of follow-up, findings from 2,194 patients indicate no significant difference in disease-free survival (DFS, P = .5), distant disease-free survival (DDFS, P = .5) or survival (S, P = .8) among the three groups. Since the outcome from AC and CMF was almost identical, the issue arises concerning which regimen is more appropriate for the treatment of breast cancer patients. AC seems preferable since, following total mastectomy, AC was completed on day 63 versus day 154 for conventional CMF; patients visited health professionals three times as often for conventional CMF as for AC; women on AC received therapy on each of 4 days versus on each of 84 days for conventional CMF; and nausea-control medication was given for about 84 days to conventional CMF patients versus for about 12 days to patients on AC. The difference in the amount of alopecia between the two treatment groups was less than anticipated. While alopecia was almost universally observed following AC therapy, 71% of the CMF patients also had hair loss and, in 41%, the loss was greater than 50%. This study and NSABP B-16, which evaluates the worth of AC therapy in TAM-responsive patients, indicate the merit of 2 months of AC therapy for all positive-node breast cancer patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Adjuvant chemoendocrine therapy in postmenopausal breast cancer: cyclophosphamide, methotrexate, and fluorouracil dose and schedule may make a difference. International Breast Cancer Study Group.

PURPOSE: Adjuvant cytotoxics prolong disease-free survival (DFS) and overall survival (OS) in patients with operable breast cancer. The first reported effective adjuvant combination regimen consisted of oral cyclophosphamide on days 1 to 14 with intravenous methotrexate and fluorouracil on days 1 and 8, repeated every 28 days (classical CMF). These drugs have since been extensively used with or without endocrine therapies and/or other cytotoxic agents. Although doses and schedules have varied widely, the combination of these three drugs is generically referred to as CMF. RESULTS: Reducing the dose and/or altering the schedule of CMF have compromised its efficacy in metastatic breast cancer. Reduction below standard dose of a similar regimen also gave inferior results in the adjuvant setting. CONCLUSION: Details of dose and schedule may therefore explain part of the heterogeneity of results observed with CMF. Particular controversy surrounds the contribution of CMF in postmenopausal women who are also receiving tamoxifen (TAM). However, the trials that demonstrated a significant benefit for the addition of CMF to TAM, even in postmenopausal women with estrogen receptor-positive tumors, used classical CMF. Therefore, adherence to the classical dose and schedule is recommended when CMF is used in adjuvant therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Estrogen and tamoxifen induce cytoskeletal remodeling and migration in endometrial cancer cells.

Much research effort has been directed toward understanding how estrogen [17beta-estradiol (E2)] regulates cell proliferation and motility through the rapid, direct activation of cytoplasmic signaling cascades (i.e. nongenomic signaling). Cell migration is critical to cancer cell invasion and metastasis and involves dynamic filamentous actin cytoskeletal remodeling and disassembly of focal adhesion sites. Although estrogen is recognized to induce cell migration in some model systems, very little information is available regarding the underlying pathways and potential influence of selective estrogen receptor modulators such as 4-hydroxytamoxifen on these processes. Using the human endometrial cancer cell lines Hec 1A and Hec 1B as model systems, we have investigated the effects of E2 and Tam on endometrial nongenomic signaling, cytoskeletal remodeling, and cell motility. Results indicate that both E2 and Tam triggered rapid activation of ERK1/2, c-Src, and focal adhesion kinase signaling pathways and filamentous actin cytoskeletal changes. These changes included dissolution of stress fibers, dynamic actin accumulation at the cell periphery, and formation of lamellipodia, filopodia, and membrane spikes. Longer treatments with either agent induced cell migration in wound healing and Boyden chamber assays. Agent-induced cytoskeletal remodeling and cell migration were blocked by a Src inhibitor. These findings define cytoskeletal remodeling and cell migration as processes regulated by E2 and 4-hydroxytamoxifen nongenomic signaling in endometrial cancer. This new information may serve as the foundation for the development of new clinical therapeutic strategies.

Actins↗