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PubMed1995

Acidic metabolites of tamoxifen. Aspects of formation and fate in the female rat.

The nonsteroidal antiestrogen tamoxifen (TAM) is subject to extensive biotransformation in humans and laboratory animals. In particular, the dimethylamino group of TAM undergoes N-demethylation and formal replacement with a hydroxyl group, affording major metabolites TAM amine and TAM alcohol, respectively. In the present study in ovariectomized rats, TAM was eliminated in part as metabolites arising from conversion of its basic side chain to an oxyacetic acid moiety. Thus, TAM acid (TA) was characterized spectrally from the urine of rats after intraperitoneal administration of TAM. TA was not detected in fecal extracts. In contrast, a second metabolite, 4-hydroxy TA (4HTA), was detected and characterized only from fecal extracts, indicative of a qualitative difference in routes of elimination for TA and 4HTA. Studies with rat liver fractions suggested TAM alcohol to be an intermediate metabolite in the conversion of TAM to TA and 4HTA. In liver microsomal fraction, TAM alcohol was converted to a novel metabolite, TAM aldehyde, which was isolated and characterized as its semicarbazone derivative. Coenzyme requirements for formation of this (derivative) metabolite, as well as for conversion of TA to 4HTA, indicated these transformations to be catalyzed by cytochromes P450. TAM aldehyde was shown to be a plausible intermediate in the formation of acidic metabolites by experiments that indicated oxidation of this to TA was catalyzed by aldehyde oxidase derived from liver cytosolic fraction.

Animals↗
PubMed1996

Determinants of tamoxifen sensitivity control the nature of the synergistic interaction between tamoxifen and cisplatin.

The cytotoxic effect of tamoxifen (TAM) was investigated in the T-289 melanoma cell line, as well as the 289 DDP3 cisplatin (DDP)-resistant and the 289 TAM6 TAM-resistant variant melanoma cell lines to determine the effect of drug resistance on synergy. T-289 melanoma cells were made DDP or TAM resistant through chronic exposure to increasing concentrations of the respective drugs. Whereas DDP resistance could be overcome by increasing the concentration of TAM, the development of TAM resistance completely abolished synergy. TAM resistance was not related to the development of estrogen receptors, decreased TAM uptake, or the increased expression of the mdr-1 gene. TAM did not inhibit the action of Topoisomerase 1; however, TAM did induce apoptosis in the 289 melanoma cells. In contrast, TAM did not induce apoptosis in the TAM-resistant variant 289 TAM6 cells. To our knowledge, these are the first data associating TAM resistance with the inhibition of apoptosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice.

The non-steroidal antiestrogen tamoxifen (TAM) is successfully used to treat all stages of breast cancer in both pre- and postmenopausal women. Unfortunately, most women treated with TAM eventually develop resistant tumor recurrences which require intervention with a second-line endocrine therapy, or cytotoxic chemotherapy if the recurrence is completely endocrine insensitive. There is evidence that some recurrences may in fact be TAM stimulated. MCF-7 human breast cancer cells grown as solid tumors in athymic mice chronically treated with TAM reproducibly develop a TAM stimulated phenotype (Osborne et al., Eur J Cancer Clin Oncol 23:1189-1196, 1987; Gottardis and Jordan, Cancer Res 48: 5183-5187, 1988; Osborne et al., J Natl Cancer Inst 83:1477-1482, 1991; Wolf et al., J Natl Cancer Inst 85:806-812, 1993). Tumors of this type may provide a useful model for a subset of therapeutic failures in the clinic. Therefore, we have extensively studied this model in an attempt to define the mechanism or mechanisms leading to TAM stimulated growth. In this paper we describe the characteristics of 4 TAM stimulated MCF-7 tumor variants. All of these tumors are growth stimulated by TAM, but vary in their response to estradiol (E2) treatment, and grow poorly in placebo treated hosts. All tumor variants express estrogen receptor (ER) RNA and protein, which at the RNA level appear to be down regulated by TAM, and to a greater extent by E2. All tumors also express epidermal growth factor receptor (EGFR) RNA, which is down regulated by TAM, and further down regulated by E2. However, among the tumor variants analyzed, ER and EGFR levels appear to be inversely related. Further, despite the expression of ER by all 4 TAM stimulated tumor variants, E2 induction of progesterone receptor expression is very weak or entirely absent.

Animals↗
PubMed1995

Effects of tamoxifen on growth and apoptosis of estrogen-dependent and -independent human breast cancer cells.

BACKGROUND: Apoptosis ("programmed cell death") is an active process characterized by prominent nuclear changes and DNA cleavage, which distinguishes it from cellular necrosis. In this study we investigated whether tamoxifen (TAM) treatment of estrogen receptor ER(+) MCF-7 and ER(-) MDA-231 human breast cancer cells resulted in cytotoxicity and cellular changes typical of apoptosis. METHODS: Cytotoxicity was measured using a tetrazolium assay. Cellular morphologic changes were observed using transmission electron microscopy. DNA cleavage was assessed using 1.6% agarose gel electrophoresis and was also quantitated biochemically. RESULTS: Exposure of cells to TAM for 24 h resulted in dose-dependent cytotoxicity, and MCF-7 cells were somewhat more sensitive to TAM. TAM induced chromatin condensation around the nuclear periphery in both cell lines, changes typical of apoptosis. TAM-induced cytotoxicity correlated with dose-dependent DNA cleavage, which showed the characteristic "internucleosomal ladder." DNA cleavage occurred at a slightly lower TAM dose and occurred somewhat sooner in MCF-7 cells. TAM-induced DNA cleavage in MCF-7 cells was inhibited by the protein synthesis inhibitor cycloheximide, the RNA synthesis inhibitor actinomycin D, and by 17 beta-estradiol. However, in MDA-231 cells, DNA cleavage was inhibited by cycloheximide, partially but not significantly inhibited by actinomycin D, and not inhibited by 17 beta-estradiol. CONCLUSIONS: TAM induces typical apoptosis in ER(+) or ER(-) human breast cancer cells. TAM induction of apoptosis in MCF-7 cells involves the estrogen receptor, and requires the synthesis of new protein and mRNA. TAM induction of apoptosis in MDA-231 cells depends primarily on protein synthesis. TAM-induced cytotoxicity and DNA damage appear to be explained in part by the induction of apoptosis.

Apoptosis↗
PubMed1985

Possible mechanisms for the agonist actions of tamoxifen and the antagonist actions of MER-25 (ethamoxytriphetol) in the mouse uterus.

Experiments were conducted to determine why tamoxifen, a non-steroidal antiestrogen, is uterotrophic in mice, whereas MER-25 (ethamoxytriphetol), a structurally related compound, is antiuterotrophic. Initial experiments indicated that the pituitary was not required for a uterotrophic response in mice to either estradiol (E2), tamoxifen (TAM), or 4-hydroxytamoxifen (4-OH-TAM) MER-25 was not uterotrophic in mice but was capable of completely inhibiting the uterotrophic responses of mice to estrogens (E2) as well as antiestrogens (TAM and 4-OH-TAM); this inhibition was reversible by increasing the dose of the antiestrogen (TAM). The relative binding affinities (RBA) of TAM, 4-OH-TAM, and MER-25 to mouse uterus estrogen receptor (ER) and mouse liver antiestrogen binding sites (AEBS) were compared to determine whether either (or both) of these sites mediate the biological effects of these compounds. E2 is arbitrarily assigned an RBA of 100 for ER; similarly, TAM is assigned an RBA of 100 for AEBS. MER-25 bound to AEBS with an RBA of 8.9 and to ER with an RBA of less than 0.06; in contrast, TAM and 4-OH-TAM bound to AEBS with RBAs of 100 and 53, respectively, and to ER with RBAs of 2 and 131, respectively. Five other compounds that had similar RBAs as MER-25 for AEBs (RBAs in the range 4-9) and for ER (RBAs less than 0.06) were tested for their antiuterotrophic activities in vivo against both estrogen (E2) and antiestrogen (TAM) in ovariectomized mice. None of these compounds were antiuterotrophic against either estradiol or tamoxifen (P less than 0.01), nor were any of the compounds uterotrophic in mice. These data suggest that differences in the biological actions of tamoxifen and MER-25 in mice are not mediated through AEBS and are most likely due to differences in their interactions with ER.

Animals↗
PubMed1985

In vivo and in vitro antiestrogenic action of 3-hydroxytamoxifen, tamoxifen and 4-hydroxytamoxifen.

This study demonstrates in vivo and in vitro properties of the non-steroidal antiestrogens tamoxifen (TAM), 4-OH-tamoxifen (4-OH-TAM) and 3-OH-tamoxifen (K 060 E). In immature rabbit uteri 4-OH-TAM and K 060 E bound to the respective estrogen receptors with a ten-fold higher affinity than TAM. Furthermore, K 060 E exhibited less agonistic (estrogenic) but higher antagonistic (antiestrogenic) activity in the immature rat uterus than TAM and 4-OH-TAM (change of uterine weight). The ratio of agonistic vs antagonistic effect of K 060 E was distinctly lower than in TAM and 4-OH-TAM. In addition, K 060 E reduced by approximately 45% the growth of the transplantable Fisher rat mammary tumor (R 3230 AC) as compared with TAM (33%). We assume that, due to the higher antitumor activity, K 060 E (3-OH-TAM) is a better antiestrogen than TAM.

Adenocarcinoma↗
PubMedDate not supplied

In the ovariectomized rat, tamoxifen conserves bone similarly in parathyroid-intact and parathyroidectomized animals.

To examine the ability of tamoxifen (TAM) to conserve bone in the estrogen-deficient ovariectomized (OVX) rat in the presence and absence of parathyroid hormone (PTH) six groups of rats with 45Ca-labeled bones were studied for 12 weeks. Rats were OVX, parathyroidectomized (PTX), or given sham operations and treated with TAM (10 mg/kg body wt./wk subcutaneously) or TAM-vehicle. Treatments were: group 1 = Sham-OVX; group 2 = Sham-OVX + TAM; group 3 = OVX; group 4 = OVX + TAM; group 5 = OVX + PTX; and group 6 = OVX + PTX + TAM. To monitor bone resorption serial measurements of urinary hydroxyproline and 45Ca excretion were made during the study. Ovariectomy raised these markers of bone breakdown and caused significant osteopenia, whereas TAM prevented ovariectomy increasing urinary hydroxyproline or 45Ca and conserved bone. Final total body calcium values (TBCa) in groups 1-6, respectively, were (mg +/- SD): 3240 +/- 300; 3260 +/- 289; 2750 +/- 231; 3212 +/- 312; 2742 +/- 199; and 3387 +/- 252. Thus ovariectomy reduced TBCa similarly in the presence and absence of the parathyroids (p < 0.001). In contrast TAM fully protected both PT-intact and PTX rats from the osteopenic effect of ovariectomy, despite the fact that PTX rats had a lower rate of bone turnover than PT-intact rats. However, TAM-treated OVX rats had shorter femora than OVX rats given TAM-vehicle, suggesting that TAM suppresses growth of the long bones to some degree in estrogen-deficient animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed2005

Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients.

Tamoxifen (TAM) is widely used for treatment and prevention of breast cancer. TAM is metabolized by cytochrome P450 (CYP450) enzymes, including CYP3A5. Although two genetic polymorphisms in CYP3A5 are known (CYP3A5*3 and CYP3A5*6), the effects of these polymorphisms on TAM metabolism, TAM side effects, and tumor characteristics are unknown. Thus, this work tested the hypothesis that CYP3A5 polymorphisms are associated with differential TAM levels, TAM side effects, and tumor characteristics in breast cancer patients. Postmenopausal women with breast cancer (n=98) were recruited from a single cancer center. Polymorphic status was established using polymerase chain reactions (PCR). The associations between polymorphic status, race, TAM levels, side effects, and tumor characteristics were assessed using t-tests and logistic regression models. The data indicate that 40.7% of the breast cancer patients had the CYP3A5*3 polymorphism, and 9.1% had the CYP3A5*6 polymorphism. In addition, Caucasian women were 26 times more likely to carry the CYP3A5*3 polymorphism than African American (AA) women, whereas AA women were nine times more likely to carry the CYP3A5*6 polymorphism than Caucasian women. No significant differences were seen in TAM or TAM metabolite levels or TAM side effects by polymorphic status. There was a significant difference, however, in mean tumor size in women with the CYP3A5*6 polymorphism (3.6+/-0.98 cm) compared to those without the polymorphism (2.0+/-0.18 cm) (P<0.02). Taken together, these data suggest that racial differences in CYP3A5 polymorphisms exist although the polymorphisms do not appear to be associated with levels of TAM metabolites and side effects.

Adult↗
PubMed1998

Inhibitory effects of uterine endometrial carcinogenesis in Donryu rats by tamoxifen.

The effects of tamoxifen (TAM) on uterine carcinogenesis were investigated in female Donryu rats. The effects were initiated by a single intrauterine treatment with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at a dose of 20 mg/kg body weight via the vagina at 10 weeks of age. TAM tubes (cholesterol tubes containing 50% TAM) were implanted into the backs of the rats for 13 months (full TAM group) or for the second-half of this period (half TAM group). In the control group treated with ENNG alone, various proliferative lesions were induced in the uterine endometrium and the incidence of endometrial adenocarcinomas was about 30%. In contrast, the uteri in both TAM-treated groups showed severe atrophy and the incidences of uterine proliferative lesions were limited to a few endometrial hyperplasias in the half TAM group. Most of the vaginas in both TAM-treated groups showed mucification, while cornification was common in the vaginal epithelium of controls. The ovaries demonstrated similar atrophy with cystic follicles and no corpora lutea in all groups. Other estrogen responsive endocrine organs, such as the pituitaries and adrenals, were small in the TAM-treated groups. Serum estrogen levels in the TAM-treated groups were lower than in the control group but progesterone levels did not differ. These results indicated that TAM acts as an anti-estrogen on the adult rat uterus, inhibiting the development of endometrial adenocarcinomas initiated by ENNG.

Adrenal Glands↗
PubMed1999

Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis.

One hundred fifty-one postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred forty-three eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p = 0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p = 0.38). Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5-year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms. Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy. The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.

Aged↗
PubMed1995

Relationship between tamoxifen-induced transforming growth factor beta 1 expression, cytostasis and apoptosis in human breast cancer cells.

Previously we have shown that tamoxifen (TAM) induces morphological and biochemical changes typical of apoptosis in oestrogen receptor (ER)-positive MCF-7 or ER-negative MDA-231 human breast cancer cells. In this study the effects of TAM on expression of transforming growth factor beta 1 (TGF-beta 1) were correlated with the effects on cell cycle kinetics and apoptosis. TAM had similar biphasic effects on both cell lines. Short-term (< 6 h) TAM incubation resulted in a slight decrease in TGF-beta 1 protein despite an increase in TGF-beta 1 mRNA and was associated with an increase in cells in S-phase. No apoptotic effects were noted. Longer (> or = 12 h) TAM incubation induced TGF-beta 1 protein (about 3-fold) and mRNA expression (about 2-fold) in both cell lines, and was associated with G1/G0 blockade and induction of apoptosis. The accumulation of TAM-induced TGF-beta 1 mRNA was increased by cycloheximide, but was not affected by 17 beta-oestradiol. Long-term incubation with TAM had no significant effect on TGF-beta 1 gene copy number. TAM-induced internucleosomal DNA cleavage was inhibited in both cell lines by the addition of an anti-TGF-beta 1 antibody. TAM has dose- and time-dependent effects on TGF-beta 1 expression associated with changes in cell cycle kinetics. These effects are independent of ER status and may be the result of a direct regulatory effect of TAM on TGF-beta 1 transcription. It also appears that induction of TGF-beta 1 plays an important role in TAM-induced apoptosis in breast cancer cells.

Antibodies, Neoplasm↗
PubMed2000

Prognostic value of tumor-associated macrophage count in human bladder cancer.

BACKGROUND: We determined the tumor-associated macrophage (TAM) count to investigate its importance in predicting clinical outcome or prognosis in patients with bladder cancer. METHODS: The TAM count and microvessel count (MVC) were determined immunohistochemically in 63 patients with bladder cancer, including 40 superficial bladder cancers and 23 invasive bladder cancers. To examine the relationship between TAM count and clinical outcome or prognosis in bladder cancer, cystectomy rates, distant metastasis rates, vascular invasion rates and 5 year survival rates were compared between patients with low (< 67) and high (> or = 67) TAM counts. RESULTS: The TAM count in invasive bladder cancers (154.22+/-11.98) was significantly higher than in superficial bladder cancers (49.05+/-7.76; P<0.0001). The MVC in invasive bladder cancers (71.55+/-10.44) was also significantly higher than in superficial bladder cancers (47.02+/-5.57; P<0.05). There was a positive correlation between TAM count and MVC (r=0.30; P=0.02). Immunohistochemical staining using CD68/horseradish peroxidase monoclonal antibody showed more infiltrating cells in invasive than superficial bladder cancers. Patients with a high TAM count (> or =67) showed significantly higher rates of cystectomy, distant metastasis and vascular invasion than those with a lower TAM count (<67). The 5 year survival rate estimated using the Kaplan-Meier method was significantly lower in patients with a high TAM count than in those with a low TAM count (P<0.0001). CONCLUSIONS: Our results suggest that determination of TAM count in bladder cancer tissues is of value to predict the clinical outcome or prognosis and to select appropriate treatment strategies in patients with bladder cancer.

Adult↗
PubMed1996

Role of c-myc in tamoxifen-induced apoptosis estrogen-independent breast cancer cells.

BACKGROUND: The antiestrogen tamoxifen (TAM) is effective in the treatment of estrogen receptor (ER)-positive as well as some ER-negative breast cancers. However, the precise mechanism of action of TAM, especially in estrogen-independent cells, remains unclear. Previous work by our laboratory has demonstrated that TAM induces the morphologic and biochemical changes that are characteristic of apoptosis in both ER-positive and ER-negative cells. PURPOSE: We compared the effect of TAM at a clinically achievable concentration on cell growth and apoptosis with the effect of TAM on c-myc (also known as C-MYC) messenger RNA (mRNA) and protein expression in ER-negative MDA-231 cells. METHODS: MDA-231 cells were treated for up to 72 hours with 1.0 microM TAM alone or in the presence of 50 microM c-myc antisense or nonsense oligonucleotides. c-myc mRNA expression was determined by northern blot analysis, protein expression by western blot analysis, cell growth inhibition counts, and DNA cleavage by agarose gel electrophoretic analysis. Differences between the mean values from different treatment groups were compared with the use of the two-sided Wilcoxon Ranksum test. RESULTS: TAM treatment for 72 hours increased c-myc mRNA five-fold (from a relative radiolabeled hybridization signal intensity of 17 +/- 4 up to 93 +/- 10; P<.05) and c-MYC protein threefold (from a relative immunofluorescence signal intensity of 28 +/- 7 up to 83+/-21; P< .05). The induction of c-myc by TAM was accompanied by internucleosomal DNA cleavage characteristic of apoptotic cell death. Addition of c-myc antisense oligonucleotide (5'CACGTTGAGGGGCAT-3') to MDA-231 cells resulted in a nearly twofold decrease of basal c-myc mRNA (P< .05) and a sevenfold decrease of basal c-Myc protein (P< .05) expression. Addition of c-myc antisense oligomer also antagonized the TAM-induced increase in c-myc mRNA (P< .05) and protein expression (P< .05) and inhibited TAM-induced cytostasis (P< .01) and apoptosis. In parallel experiments, addition of the nonsense oligomer had no effect on any of the measured parameters. CONCLUSIONS: These results indicate that the effects of TAM on ER-negative MDA-231 cells may be mediated through c-myc overexpression. c-myc may play a critical role in the growth and progression of MDA-231 breast cancer cells.

Antineoplastic Agents, Hormonal↗
PubMed1999

Characterization of a human melanoma cell line with non-oestrogen receptor dependent tamoxifen resistance.

While investigating the mechanism of synergistic cytotoxicity between tamoxifen (TAM) and cisplatin (DDP) we developed a TAM-resistant variant of the human melanoma cell line T-289. We sought to characterize this cell line with respect to the effect of TAM resistance on a variety of different intracellular cell cycle control and apoptotic pathways. A TAM-resistant variant cell line (289 TAMs) was developed and the technique of Western analysis was to determine the changes in protein expression that occurred as a result of the development of TAM resistance. In this model, TAM resistance resulted in an increase in the detectable basal levels of cyclin E, GADD 153, p16, BAX, Bcl-XL, and wild-type and mutant p53, an increase in TAM induction of p16, and a decrease in the detectable basal levels of cyclin D1, p21 and p27. There were no detectable changes in the levels of pRb. In the TAM-resistant variant, p21 levels were essentially undetectable, while p27 was present and maintained its response to TAM Induction, albeit at a much lower level. This investigation demonstrates that the development of TAM resistance is associated with a change in the detectable levels of a variety of cell cycle control and apoptosis-related proteins. While the exact role that each change plays in the development of tamoxifen resistance remains to be determined, these data suggest that the development of resistance to a particular agent results in changes in multiple, seemingly unrelated pathways. These data have implications for future studies in both the laboratory and the clinic.

Antineoplastic Agents, Hormonal↗
PubMed2004

Dietary flaxseed enhances the inhibitory effect of tamoxifen on the growth of estrogen-dependent human breast cancer (mcf-7) in nude mice.

PURPOSE: This study determined the effect of 10% dietary flaxseed (FS) and tamoxifen (TAM), alone and in combination, on the growth of estrogen-dependent human breast cancer (MCF-7) in athymic mice with or without 17beta-estradiol (E2) supplementation. EXPERIMENTAL DESIGN: Ovariectomized mice received injection with MCF-7 cells, were implanted with an E2 pellet (1.7 mg), and fed the basal diet (BD). When tumor reached approximately 40 mm2, the E2 implant was removed, and mice were randomized to the following groups and maintained at either low (E2 pellet removed) or high E2 level (new E2 pellet implanted) for 6 weeks: (a) positive control with new E2 pellet, fed BD, (b) negative control with no E2 implant, fed BD, (c) TAM group with TAM pellet (5 mg) implant, fed BD, (d) FS group fed 10% FS, (e) FS+TAM group with TAM implant, fed 10% FS. Tumor growth was monitored weekly. RESULTS: At low E2 level, FS regressed the pretreatment tumor size by 74%. TAM regressed tumor initially but later induced an increase so that the tumor size was finally similar to the pretreatment size. A tumor regression >53% was induced by FS+TAM than by TAM alone. At high E2 level, FS, TAM, and FS+TAM inhibited the tumor growth by 22, 41, and 50%, respectively, compared with the positive control. Decreased tumor size was attributable to reduced tumor cell proliferation and increased apoptosis. CONCLUSIONS: FS inhibited the growth of human estrogen-dependent breast cancer and strengthened the tumor-inhibitory effect of TAM at both low and high E2 levels.

Animal Feed↗
PubMed1998

Side effects of tamoxifen in oophorectomized rats.

OBJECTIVE: Our objective was to evaluate the direct effect of tamoxifen citrate (TAM) on the endometrium, liver, breast tissue and the lipid profile in oophorectomized (OX) rats. STUDY DESIGN: An experimental animal study. MATERIAL AND METHODS: Forty-one mature rats (33 OX) were randomly divided into four groups and received either TAM (0.4 or 0.8 mg/kg p.o.) therapy or placebo over 60 days as follows: (1) sham; (2) OX + TAM (0.4 mg/kg); (3) OX + TAM (0.8 mg/kg); (4) OX. All histological changes in the endometrium, liver and breast tissue were evaluated under the light microscope by comparing the TAM-treated groups with the OX and sham-operated groups. Blood total cholesterol and low-density lipoprotein cholesterol levels were also analyzed. RESULTS: TAM-treated rats showed a significant reduction in body weight, blood cholesterol and low-density lipoprotein cholesterol levels, but the wet uterine weight was not affected. Estrogenic effects of TAM were not detected with either dosage on the endometrium. TAM-treated groups showed atrophic breast tissue. No histopathological changes were detected in the liver with TAM treatment. CONCLUSION: The data suggests that TAM may not act as an estrogen receptor agonist with the given dosage on the endometrium in OX rats. Two different doses of TAM do not cause histological changes in liver over 60 days of treatment.

Animals↗
PubMed1991

The role of macrophages in the regulation of primary tumor growth.

Tumor-associated macrophages (TAM) represent a population of tissue macrophages with peculiar biological, biochemical and phenotypic properties. Here we have briefly analyzed two different mechanisms involved in the regulation of the levels of TAM: the production of tumor-derived chemotactic factors for mononuclear phagocytes and in situ proliferation of TAM. Two clones selected from the murine sarcoma line B77 showed a different capacity to produce the tumor-derived chemotactic factor known as JE. Studies with these clones demonstrated a correlation between in vitro production of the protein JE, expression of JE mRNA and macrophage content in tumor tissues, suggesting that the production of chemotactic factors can play a role in the regulation of TAM accumulation. Moreover, it has been shown that TAM had high levels of proliferative activity compared to peritoneal exudate macrophages. In an effort to elucidate the mechanisms responsible for the proliferative activity of TAM, the expression of c-fms and macrophage-colony-stimulating factor (M-CSF) was investigated in TAM and sarcoma cells. TAM had high levels of mRNA transcripts of the c-fms protooncogene, which encodes a tyrosine kinase probably identical to the M-CSF receptor, but did not express M-CSF transcripts, while sarcoma cells had high levels of M-CSF mRNA. Sarcoma-cell-conditioned medium had M-CSF activity on bone marrow cells: this activity was blocked by anti-M-CSF antibodies. These findings outline a paracrine circuit in the regulation of TAM proliferation, involving M-CSF secreted by sarcoma cells and acting on c-fms-expressing TAM. A better understanding of the regulation and function of TAM may provide a less empirical basis for a rationale design of therapeutic approaches.

Animals↗
PubMed2026

Tumor-associated macrophages display differential protein cargo sorting in extracellular vesicles associated with poor survival in ovarian cancer.

Ovarian cancer (OC) progression and metastasis are promoted by ascites, which constitutes a central part of the tumor microenvironment (TME). In this fluid, tumor-associated macrophages (TAMs) represent a prominent immune cell type. In addition to tumor and other host cells such as TAMs, ascites is highly enriched in soluble factors as well as extracellular vesicles (EVs). How TAMs contribute to the EV compartment of the OC TME remains, however, underexplored. In this work peripheral blood monocytes from healthy donors were differentiated into monocyte-derived macrophages (MDMs) and polarized into classically activated (M1-like), alternatively activated (M2-like) and TAM-like (by ascites incubation). For all subtypes, serum-free conditioned medium was collected for 24&#xa0;h and EVs were isolated and characterized by nano-flow cytometry (nFC), label-free mass spectrometry-based proteomics and electron microscopy, among others. Our results demonstrated distinct traits for EV release and cargo across the different macrophage subtypes. Specifically, TAM-like macrophages exhibited impaired release of small EVs and reduced frequency of tetraspanin-positive particles. These EV subpopulations displayed sizing profiles closer to M1-like than to M2-like samples. Also, the low EV release in TAM-like MDMs was accompanied by altered expression of biogenesis-related markers like flotillin-1 (FLOT1) and a decreased N-glycosylation of CD63 protein, which was validated in patient-derived samples. Remarkably, the EV-associated proteome of TAMs displayed significant enrichment in both pro- and anti-inflammatory molecules with clinical value. Markers significantly enriched in the ascites TAM-EV signature were mostly associated with poor prognosis, whereas M1-like EV-related markers (pro-inflammatory) were mostly associated with longer survival. Our results confirmed previous data for proteins like CD163 and MRC1 to be associated to TAM-EVs, while also describing novel candidates with diagnostic (i.e., COLEC12) and/or prognostic (i.e., MSR1) value in plasma. Taken together, our data support a unique secretory profile of TAMs in OC and provide new EV-associated biomarkers with translational impact. Our results pave the way for a better understanding of the mechanisms behind TAM-EV cargo loading and function, and how these cells participate in the TME landscape.

Humans↗