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PubMed2006

The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma.

BACKGROUND AND OBJECTIVES: The presence of tumor-associated macrophages (TAM) is a prognostic factor for survival in follicular lymphoma (FL). Overexpression and/or activation of the signal transducer and activator of transcription 1 (STAT1) in these TAM have also been observed. The aim of this study was to determine the extent to which macrophages are present in FL and to investigate the expression of STAT1 in these cells. DESIGN AND METHODS: We retrospectively analyzed 211 patients with distinct stages and grades of FL. Expression of the CD68 proteins, chosen as a marker for macrophages, and STAT1 was quantified by immunohistochemistry and double immunofluorescence. RESULTS: Automated determinations revealed the presence of CD68-positive macrophages in all FL tissues studied (mean 57.6+/-45.1 cells/field), while STAT1 protein was expressed in 29.94% of cases. Double-fluorescence staining confirmed that STAT1 protein co-localized exclusively with CD68, indicating the presence of a subset of STAT1-expressing TAM localized principally in the vicinity of tumor cells. Multivariate analysis showed that, besides the Follicular Lymphoma International Prognostic Index (FLIPI) classification, expression of STAT1 was an important independent prognostic factor for shorter overall survival in FL. INTERPRETATION AND CONCLUSIONS: These results demonstrate the presence of STAT1-expressing TAM in FL and their association with an adverse outcome, thus emphasizing the relevance of non-tumor cells in the control of the growth and survival of lymphoma cells.

Aged↗
PubMed1992

Role of tamoxifen in the induction of hormone-independent rat mammary tumors.

Using the dimethylbenzanthracene-induced rat mammary tumor model, we examined the appearance and growth of tumors in animals given tamoxifen (TAM) either coincident with dimethylbenzanthracene or after initial tumor formation. While fewer tumors arose after coadministration of antiestrogen and carcinogen and TAM treatment caused regression of most existing tumors, new tumors developed in the presence of TAM in both studies. Since none of these new tumors regressed following ovariectomy, all were classified as hormone independent. Furthermore, these independent tumors grew more rapidly than both control-dependent and independent tumors, resulting in a greater average volume. These data suggest that a more aggressive form of hormone-independent tumor appears during TAM treatment.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Tumour adjacent macrophage function in experimental tumours.

This study describes in vivo methodology for evaluating whole body and Tumour Adjacent Macrophage (TAM) phagocytic function in tumour-bearing rats. 29 Wistar rats were inoculated with 1 x 5 mm cylinders of syngeneic NGW-adenocarcinoma im in the right hind leg. 10 rats were given iv zymosan (3mg/100 g b.w.) for systemic activation of macrophages, 9 rats were given intratumour injection of zymosan (3mg/100g b.w.) for local activation and 10 rats were untreated controls. 10 days after tumour inoculation whole body phagocytic rate was estimated with dynamic liver RES scintigraphy. Tumour and blood radionuclide activity was measured. Dynamic liver RES scintigraphy measures whole body macrophage phagocytic rate (k) of iv 99Tcm Nanocoll albumin test colloid. TAM phagocytic rate is calculated from the final uptake in tumor/injected dose x k. Systemic macrophage activation caused a significant increase in liver and spleen weight and whole body phagocytic rate (0.65 +/- 0.02 versus 0.56 +/- 0.03% s-1). The TAM phagocytic rate was significantly elevated in tumors treated by local macrophage activation (0.003 +/- 0.00 versus 0.001 +/- 0.00% s-1). This study suggests that the TAM phagocytic rate is a sensitive indication of local macrophage activity.

Adenocarcinoma↗
PubMed1989

[Results of tamoxifen-medroxyprogesterone acetate sequential therapy in 22 patients with recurrent breast cancer].

Effects of tamoxifen (TAM)-medroxyprogesterone (MPA) sequential therapy were evaluated in 22 patients with recurrent breast cancer. TAM-MPA therapy was given in the form of TAM 20 mg b.i.d. for 14 days followed by MPA 1200 mg t.i.d. for the subsequent 14 days, in alternating sequence. The response rate was 27% (6/22). Weight gain (greater than 5 kg) was observed in 18% (4/22) and this incidence was lower than that reported for MPA therapy. These results demonstrate that TAM-MPA therapy offers fewer side effects than MPA therapy, but response rate is unlikely to be improved.

Adult↗
PubMedDate not supplied

[Antiestrogens in the treatment of advanced breast cancer].

Fifty nine female patients with an advanced, recurrent breast cancer were treated with tamoxifen (TAM) in the daily dose of 40-60 mg. The drug was administered to 44 patients following ineffective chemotherapy and/or hormonotherapy with stilbestrol. Ineffective therapy was related with the deterioration of the general status. TAM was administered to the remaining 15 patients from the beginning due to the serious condition. Twenty four patients with the advanced breast cancer treated according to FAC regimen served as the control group. TAM produced significant improvement in health status of the majority of the treated patients and partial remission of cancer in 30% of them. Incidence of remissions, duration and survival period in patients treated with TAM for the advanced breast cancer did not differ significantly from the results obtained in the control group.

Adult↗
PubMed1985

Effective sequential administration of tamoxifen and medroxyprogesterone acetate for 7,12-dimethylbenz[a-anthracene-induced rat mammary tumors in relation to hormone receptors.

The effects of two hormonal agents with different mechanisms of action, medroxyprogesterone acetate (MPA) and tamoxifen (TAM), on the tumor growth and hormone receptor status were evaluated in rat mammary tumors induced by 7,12-dimethylbenz[alpha]anthracene (DMBA). All estrogen receptor-positive (ER(+)) tumors became ER-negative (ER(-)), and 3 out of 4 progesterone receptor-negative (PgR(-)) and ER(+) tumors became PgR-positive (PgR(+)) after daily, oral administration of TAM for 2 weeks. In contrast, ER and PgR remained unchanged after daily administration of MPA for 2 to 4 weeks. All the ER(+) and PgR(-) tumors were transformed into PgR(+) after daily treatment with MPA for 2 weeks and then with TAM for another 2 weeks, but tumor regression was modest and none disappeared completely. In contrast, complete remission was achieved in all ER(+) tumors in the group treated with TAM for 2 weeks and then with MPA for another 2 weeks. The results suggest that the antitumor activity of the latter treatment regimen was significantly higher than that of the former. The possible mechanisms of antitumor activity of two hormonal agents are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Hormone dependency of human breast neoplasms cultured in vitro in the stem cell assay.

The stem cell soft agar culture system provides a biological tool with which to study tumor clones derived from heterogeneous tumor cell populations. For testing the feasibility of this approach in identifying hormone-responsive clones of mammary tumors, a study was done to determine whether estrogen deprivation or supplementation would alter colony formation in sequential breast neoplasms received in the Cell Kinetics Laboratory, The Pennsylvania State University. Single-cell suspensions obtained from 22 freshly excised breast neoplasms (20 malignant, 2 benign) were plated in soft agar with and without tamoxifen (Tam) (10(-7) M) with the use of serum-supplemented media and with and without 17 beta-estradiol (E2) (10(-8) M] under serum-free medium conditions. Twenty tumors successfully grew, producing 42 +/- 8 (mean +/- SEM) colonies in control dishes in the presence of serum and 27 +/- 5 in its absence (P less than .001). Tam inhibited colony formation in 78% of malignant tumors, whereas a stimulatory effect was observed with E2 in 94%. An increase in colony formation was induced by Tam in 4 tumors (2 benign and 2 malignant). The effects of E2 and Tam on tumor growth were not influenced by the estrogen and progesterone receptor status of the tumor. These preliminary results suggest that all tumors, irrespective of their receptor status, may contain clones of hormone-responsive cells.

Adenocarcinoma, Mucinous↗
PubMed1985

[Chemo-endocrine therapy of diffuse carcinoma of the stomach and its clinical evaluation].

UNLABELLED: Based on experimental study that some human gastric cancers do contain measurable estrogen receptor (ER) and the growth of diffuse carcinoma of the stomach on nude mice depended on sex hormone. Chemo-endocrine therapy after gastrectomy for female patients are starting since 1980. RESULTS: 1) The cumulative 2, 3 and 4 year survival rate in 8 patients with chemo-endocrine therapy (TAM+) revealed significant higher (100%, 80% and 53.4%) than those (59.2%, 23.7% and 0%) in 10 patients with chemotherapy alone (TAM-) after curative gastrectomy. Average disease free interval showed two times longer (32.0 m0) in TAM(+) than those (15.3 m0) in TAM(-). There was no significant on survival rate in both groups of noncurativelly resected patients. 2) Patients with higher ER contents (greater than or equal to 3.0 fmols) have a tendency with favorable prognosis and better response to chemo-endocrine therapy.

Adenocarcinoma, Scirrhous↗
PubMed1988

Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal human breast cells in culture.

Estradiol and triphenylethylene antiestrogen actions have been studied extensively in breast cancer cell lines. However, their effects are still poorly understood on normal human breast cells. We have developed a culture system of normal human breast epithelial (HBE) cells. It has been shown previously that cultured HBE cells were hormone dependent and well adapted for the study of hormone/antihormone actions. However, until now, no data were available on estradiol receptor (ER) in HBE cells. In this study, the presence of ER was demonstrated by (a) whole-cell biochemical assay on breast cells after enzymatic tissue dissociation and (b) an immunocytochemical method using an anti-ER monoclonal antibody both on enzymatically dissociated cells and on 8-day cultured cells. Immunostaining was nuclear and cell positivity was heterogeneous. However, the percentage of positive cells and staining intensity were far greater in the presence of estradiol in the culture, indicating estradiol stimulation of ER. Moreover, HBE cells were used to study the action on cell growth of estradiol versus trans-tamoxifen (TAM), trans-4-hydroxytamoxifen (trans-4OHTAM), and cis-4-hydroxytamoxifen (cis-4OHTAM) alone or added to estradiol. Cell growth was estimated daily by a histometric method and by DNA assay at the end of the 7-day study. When the medium was minimally supplemented with human serum (1%), estradiol stimulated cell growth in a dose-dependent manner at concentrations varying from 10(-9) to 10(-7) M. TAM and trans-4OHTAM clearly inhibited mammary cell division when estradiol was added to the medium and, to a lesser extent, in the absence of estradiol. This inhibitory effect was dose dependent. trans-4OHTAM was 100 times more active than trans-TAM. cis-4OHTAM also clearly inhibited breast cell division at 10(-7) and 10(-6) M concentrations but was 3-fold less efficient than trans-4OHTAM. In conclusion, (a) the presence and estradiol dependence of ER have been demonstrated in HBE cells, which constitute a fruitful model for the study of hormone/antihormone actions, and (b) in these normal cells, estradiol stimulates growth, whereas TAM and the 4OHTAM isomers are potent inhibitors of cell multiplication, as they are in breast cancer cell lines in culture.

Breast↗
PubMed1985

Prolactin levels and hormonal profile in postmenopausal patients with advanced breast cancer during endocrine treatments.

Seventy postmenopausal patients with advanced breast cancer, the majority not having been pretreated, underwent a hormonal profile study (LH, FSH, PRL, E2, testosterone, TSH, T3, T4, FT3, FT4 serum levels) by RIA standard methods. The result was that these patients had the same mean hormonal profile of normal controls. The hormonal profile was studied in 66 patients before and after one month of treatment with medroxyprogesterone acetate at high doses (MAP h.d.) (45 patients), tamoxifen (TAM) (10 pts.) and MAP h.d. + TAM + bromocriptine (MTB) (11 pts.). No significant difference in the pre-treatment hormonal profile was observed in either patients who responded to the subsequent treatment or in those who did not. MAP h.d. induced a marked inhibition of gonadotropins, E2, testosterone, T3, T4 while PRL, TSH and FT3 remained unchanged and FT4 increased. TAM induced a decrease of gonadotropins and T4 while all the other hormones remained unchanged. MTB induced the same effects of MAP h.d. as well as a decrease of PRL serum levels. All hormonal variations except PRL occurred independently of the clinical response. A particular behaviour of PRL was evident after one month of treatment with MAP h.d. and TAM: patients who did not respond had a statistically significant increase of PRL serum levels while in responders the PRL serum levels decreased or remained unchanged. Specifically 24 out of 28 (86%) patients with an increase greater than 20% of the PRL levels were non-responders.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Induction of tumor associated macrophage-mediated lysis of autologous tumor cells by lectins.

Lectin dependent cell mediated cytotoxicity (LDCC) to autologous tumor cells (ATC) by the tumor associated macrophages (TAM) was studied by 4 h 51Cr release assays at early and late stages of growth of a murine transplantable ascites tumor, S-180, in presence of different concentrations of wheat germ agglutinin (WGA) and Concanavalin A (Con A). Induction of LDCC by the unstimulated resident macrophages (RM) to S-180 tumor cells was also assayed. Both WGA and Con A induced significant tumoricidal activity in the TAM at different states of activation and in RM in a dose-dependent manner, the activated TAM showing expression of cytotoxicity with the lowest doses of the lectins used. Addition of N-acetylglucosamine (NAcGle) or D-mannose (D-man) in the assay completely inhibited LDCC induced by WGA and Con A, respectively. Effector-target contact alone not sufficient for inducing lysis in LDCC was evident from the observations that low doses of the lectins augmented target binding by the inactivated TAM and RM with no subsequent cytolysis.

Animals↗
PubMed1986

Adjuvant tamoxifen in postmenopausal high-risk breast cancer patients: present status of Danish Breast Cancer Cooperative Group trials.

The aim of the present study was to analyze the efficacy of adjuvant tamoxifen (TAM) in postmenopausal patients with high-risk breast cancer. The primary surgical treatment was total mastectomy with axillary sampling. There were 1,650 eligible patients; 829 were randomized to receive postoperative radiotherapy (RT) and 821, to receive RT + TAM (10 mg three times daily for 1 yr). The 2 groups were identical with respect to age, tumor size, number of positive lymph nodes, degree of anaplasia, and estrogen and progesterone receptor content. Overall recurrence-free survival at 6 years was 39% in the RT group, compared to 48% in the RT + TAM group (P = 0.0008), but there was no significant difference in survival (P = 0.14). From retrospective analyses of recurrence-free survival according to prognostic variables, it appears that 4 subgroups of patients benefited from adjuvant TAM: those less than 69 years of age, those with 4 or more positive nodes, those with grade I-II tumors, and those with high estrogen receptor values (greater than 100 fmol/mg cytosol protein).

Aged↗
PubMed1987

Inhibition by monosaccharides of tumor associated macrophages mediated antibody dependent cell cytotoxicity to autologous tumor cells.

A number of mono- and oligosaccharides are known to inhibit direct contact mediated cytotoxicity of natural killer cells, cytotoxic T lymphocytes and macrophages. In antibody dependent cell mediated cytotoxicity (ADCC), where antibody molecules mediate target recognition, binding and lysis, the role of cell surface carbohydrates is not clearly defined. In the present paper the effects of D-mannose (D-man), N-acetylglucosamine (N-AcGlc), N-acetylgalactosamine (N-AcGal) and glucose on binding and lytic events of ADCC by the tumor associated macrophages (TAM) to autologous tumor cells (ATC) were studied. The TAM were isolated on day 3 of growth of a transplantable ascites tumor--S-180, in Swiss mice. D-man, N-AcGlc and N-AcGal when added to the assay partially inhibited ADCC at 15 mM but at 25 and 40 mM totally abrogated ADCC. Glucose marginally enhanced ADCC at 25 mM but at other concentrations partial inhibition of ADCC occurred. Preincubation of TAM with 25 mM of D-man, N--AcGlc and N-AcGal resulted in total abrogation of ADCC with significant reduction in their binding of ATC, whereas, pretreatment of ATC with the sugars produced 30-40% inhibition of lysis with marginal reduction in target binding. The inhibitory effects of D-man, N-AcGlc and N-AcGal were also observed on ADCC mediated by the peritoneal resident macrophages (RM) of Swiss mice. "Lectin-like" receptors were postulated to be present on the surface of TAM which were involved in ADCC and were inhibitable by sugars.

Acetylgalactosamine↗
PubMed1986

Influence of tamoxifen and estradiol on the growth of human breast cancer cells in vitro.

Cells obtained from freshly resected human breast cancer were grown in vitro utilizing the soft agar technique. The effects of adding an antiestrogen (tamoxifen, TAM) and 17 beta-estradiol alone or simultaneously on cell growth were assessed. The addition of TAM (10(-6) M) to the medium resulted in a significant decrease in cell growth in 26 of 36 (72%) estrogen receptor (ER)-positive tumors and in one of 5 ER-negative tumors (20%). The degree of inhibition caused by TAM was significantly higher in the ER-positive tumors that also contain the progesterone receptor (PgR) as compared to those that lacked that receptor (i.e., PgR negative) (46.2 +/- 2% versus 36.2 +/- 1.2% inhibition, P less than 0.01). The simultaneous addition of 17 beta-estradiol (10(-8) M) neutralized the inhibitory effect of TAM (10(-6) M) in the majority of tumors. With the presence of serum in the medium, the addition of 17 beta-estradiol alone resulted in an enhancement of cell growth in 6 of 17 tumors. However, because of the confounding effects of serum in the medium, we studied the individual effect of 17 beta-estradiol (10(-8) M) when added alone under serum-free conditions. Of 20 tumors studied, 17 beta-estradiol significantly enhanced cell growth in 12. There was a 67.8 +/- 12.6% increase in the number of colonies formed in these 12 responding tumors. One of these 12 responding tumors was ER negative as well as PgR negative, while the rest were all ER positive. These in vitro studies demonstrate that this approach can provide valuable information on endocrine mechanisms controlling the growth of human breast cancer.

Breast Neoplasms↗
PubMed1986

Hormone steroid receptor variation after tamoxifen administration in endometrial adenocarcinoma from postmenopausal patients.

Cytoplasmic and nuclear variations of estrogen (ER) and progesterone receptors (PgR) induced by tamoxifen (TAM) treatment were investigated in 38 postmenopausal women with endometrial carcinoma. The treatment consisted of a daily oral administration of 40 mg for 7 days. Tumor samples from each patient were withdrawn before TAM administration under hysteroscopy and at the time of hysterectomy. Cytoplasmic and nuclear receptors were respectively determined by the dextran-coated charcoal assay and the hydroxylapatite technique. In the cytoplasmic fraction no significant change in mean ER value was observed, but a statistically significant increase in PgR was found (P less than 0.001). Conversely, in the nuclear fraction PgR did not vary, but a significant increase in ER content (P less than 0.001) was observed. PgR, analyzed by sucrose density gradient after TAM, showed the same sedimentation property (9 S) as the preexisting receptor, but with a single peak profile, indicating a lower heterogeneity. Our data support the hypothesis that the mechanism of PgR synthesis is induced by the ER-TAM complex and suggest the possibility of increasing the PgR content in these patients for sequential endocrine therapy.

Adenocarcinoma↗
PubMed1985

Photoaffinity labeling of the progesterone receptor from human endometrial carcinoma.

A nude mouse model for the growth of human endometrial carcinoma and hormonal modulation of the progesterone receptor (PR) was established previously. This study describes the effect of 17 beta-estradiol and tamoxifen (TAM) on growth rate and PR concentration in a hormonally responsive human endometrial tumor (EnCa 101) grown in this experimental system and presents the first characterization of human endometrial carcinoma PR. EnCa 101 was transplanted subcutaneously into ovariectomized, BALB/c, nu/nu athymic mice and grown under 17 beta-estradiol-stimulated, TAM-stimulated, and control conditions. Both 17 beta-estradiol and TAM increased the growth rate of EnCa 101 in nude mice, and a parallel increase in the cytosol PR concentration was observed, from 130 +/- 55 (SD) fmol/mg protein to 1,311 +/- 598 fmol/mg protein and 710 +/- 310 fmol/mg protein, respectively. PR was partially purified by phosphocellulose and DEAE cellulose chromatography, and the DEAE eluate was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and photoaffinity labeling with [17 alpha-methyl-3H]promegestone ([3H]R5020). Two PR-negative tumors (EnCa K and EnCa V) were also examined in parallel. Coomassie blue staining of gels revealed that the protein patterns of all of the partially purified preparations from EnCa 101, EnCa K, and EnCa V were essentially identical. In contrast, photolabeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of EnCa 101 grown in the presence of 17 beta-estradiol or TAM revealed incorporation of [3H]R5020 into proteins of molecular weight approximately 116,000 and 85,000. Labeled proteins of molecular weight 66,000, 45,000, and 35,000 were also observed. In each case, the labeling was competable with excess non-radioactive R5020. No incorporation of [3H]R5020 was observed in EnCa 101 grown in the absence of estrogen, nor was any observed in EnCa K or EnCa V.

Affinity Labels↗
PubMed1984

[Sex hormone dependency in diffuse carcinoma of the stomach and results of chemo-endocrine therapy].

Based on experimental study that the growth of diffuse carcinoma of the stomach depended on sex hormone, chemo-endocrine therapy using an anti-estrogen after gastrectomy for female patients are carrying out in National Cancer Center Hospital since 1980. The results are as follows. The cumulative 3 year survival rate in 21 patients with chemo-endocrine therapy (TAM+) revealed significant higher (45.8%) than those (7.4%) in 23 patients with chemotherapy alone (TAM-). The results of TAM(+) in curatively resected cases (8 cases) were both 100% of 2 and 3 year survival rate with 2 recurrent cases. In TAM(-) 10 cases, 2 and 3 year survival rate showed 56.0% and 20.0% respectively (P less than 0.01). This study suggests that the chemo-endocrine therapy may be a new adjuvant therapy in female patients with diffuse carcinoma of the stomach.

Adenocarcinoma, Scirrhous↗
PubMed1983

Effects of alterations in early hormonal environment on development and hormone dependency of carcinogen-induced mammary tumors in rats.

The purpose of this study was to determine the early role of estrogen and prolactin on subsequent hormone dependency of carcinogen-induced mammary tumors. Virgin 57-day-old Sprague-Dawley rats were given i.v. injections of 7,12-dimethylbenz(a)anthracene (DMBA). One day prior to and 7 days after DMBA administration, the rats were divided into separate groups and given: a daily 0.1-ml s.c. injection of vehicle (controls); haloperidol (0.5 mg/kg) to increase prolactin secretion; estradiol benzoate (1 microgram/rat) to increase estrogen levels; bromocryptine (5 mg/kg) to inhibit prolactin release; tamoxifen (TAM, 20 micrograms/rat) to inhibit estrogen action; or the combination of TAM and bromocryptine. Drug and hormone treatments were terminated after 8 days. Sixteen weeks after DMBA administration, all animals were bilaterally ovariectomized, and 4 weeks later it was determined whether the mammary tumors were hormone dependent or independent. Treatment with TAM resulted in a significant reduction in incidence of mammary tumors, but also a 3-fold increase in the percentage of these tumors that showed hormone independence after ovariectomy as compared with that of control rats. Rats treated with the combination of TAM and bromocryptine also showed a significant reduction in tumor incidence and number, but a 5-fold greater percentage of hormone-independent tumors after ovariectomy. Rats given daily injections of haloperidol or estradiol benzoate showed only small differences in mammary tumor incidence or autonomy after ovariectomy, as compared with controls given injection vehicle alone. These results suggest that rats made deficient in estrogen and prolactin at the time of DMBA administration develop fewer tumors, but the tumors that develop are not dependent on these hormones for subsequent growth.

9,10-Dimethyl-1,2-benzanthracene↗