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European Review For Medical and... Nov 2019The pathogenesis of tongue cancer (TA) has not been fully illustrated. Cyclooxygenase-2 (COX-2) is correlated with the precancerous lesion of oral cavity mucosa and...
OBJECTIVE
The pathogenesis of tongue cancer (TA) has not been fully illustrated. Cyclooxygenase-2 (COX-2) is correlated with the precancerous lesion of oral cavity mucosa and malignant transformation. The focal adhesion kinase (FAK) and gap junction protein connexin 43 (Cx43) are involved in the occurrence and progression of tumors. This study aimed to investigate the effect of celecoxib on the proliferation, malignant transformation, and expression of FAK and Cx43 proteins.
MATERIALS AND METHODS
Healthy male Sprague-Dawley (SD) rats (4 months old) were divided into control, model and celecoxib group. 7,12-dimethylbenzanthracene (DMBA) was used to generate tongue mucosal carcinoma, coupled with celecoxib intervention. At 8, 12, 16, and 20 weeks after induction, the rat survival status, the tumor formation rate and the tongue tissue morphology were observed. Meanwhile, the expression of FAK and Cx43 was also evaluated by using immunohistochemistry (IHC).
RESULTS
Tumor occurrence rates after induction were 0, 26.67%, 66.67%, and 80% at 8, 12, 16, and 20 weeks, respectively. The celecoxib treatment decreased such rats to 0, 0, 0, and 13.33%, respectively (p<0.05 compared to model group). No significant change was observed in control group, whilst model group had mild to severe hyperplasia and squamous carcinoma with elongated time. Celecoxib treatment significantly improved the tissue morphology (p<0.05). The model group also had elevated FAK and depressed Cx43 protein expression (p<0.05). With elongated time, the FAK expression was further increased whilst Cx43 protein was depressed (p<0.05 compared to model group).
CONCLUSIONS
The focal application of celecoxib effectively inhibited the DMBA-induced rat TA, possibly via regulating FAK and CX43 protein expression, and inhibiting oral epidermal hyperplasia.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Celecoxib; Connexin 43; Disease Models, Animal; Focal Adhesion Kinase 1; Injections, Intraperitoneal; Male; Rats; Rats, Sprague-Dawley; Tongue Neoplasms
PubMed: 31773683
DOI: 10.26355/eurrev_201911_19439 -
Cancer Prevention Research... Feb 2020Breast cancers evolve in a multistage process that can span decades after a carcinogenic exposure. It follows that long-lived precursor breast lesions persist in a...
Breast cancers evolve in a multistage process that can span decades after a carcinogenic exposure. It follows that long-lived precursor breast lesions persist in a subclinical state prior to completing malignant transformation, yet widely used breast cancer models lack an experimental framework for targeting premalignant disease. Inspired by classic multistage skin carcinogenesis protocols, we combined chemical carcinogenesis with transgenic mouse modeling to resolve mouse mammary carcinogenesis into discrete initiation and progression stages. At the initiation stage, exposure to the carcinogen 7,12-dimethylbenzanthracene (DMBA) generated "initiated mammary epithelial cells" (iMEC) by introducing a stereotyped driver mutation. Whether DMBA exposure occurred during puberty or adulthood, mice efficiently acquired iMEC clones that eluded detection by conventional histology, yet were long lived, persisting in a clinically silent state for months in the absence of a cooperating event. At the progression stage, inducible activation of oncogenic Wnt signaling drove rapid and synchronous transformation of latent iMECs into overt mammary carcinomas, while Wnt activation in neighboring normal mammary epithelium yielded only benign hyperplasia over this same time period. Although early parity (completion of a full-term pregnancy) reduces breast cancer risk in some contexts, standard parity-induced protection schemes failed to eliminate iMECs in our multistage model, suggesting Wnt-responsive iMECs are maintained by hormone-independent mechanisms. Variations on our multistage modeling strategy may help to identify and validate cellular and molecular targets for breast cancer chemoprevention.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Clone Cells; Disease Progression; Epithelial Cells; Female; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Mutation; Parity; Pregnancy; Proto-Oncogene Proteins p21(ras); Time Factors; Wnt Signaling Pathway; Wnt1 Protein
PubMed: 31699706
DOI: 10.1158/1940-6207.CAPR-19-0322 -
Carcinogenesis Jul 2020Previous studies demonstrate that the heavy metal cadmium and the metalloid arsenite activate estrogen receptor-alpha in breast cancer cells by forming a high-affinity...
Previous studies demonstrate that the heavy metal cadmium and the metalloid arsenite activate estrogen receptor-alpha in breast cancer cells by forming a high-affinity complex with the ligand-binding domain of the receptor and that environmentally relevant doses of cadmium have estrogen-like activity in vivo. The present study showed that in estrogen-receptor positive cells, arsenite and cadmium increased the global expression of estrogen-responsive genes and that an environmentally relevant dose of arsenite also had estrogen-like activity in vivo. Similar to estrogens, exposure of ovariectomized animals to arsenite induced the expression of the progesterone receptor, GREB1, and c-fos in the mammary gland and the expression of complement C3, c-fos, and cyclin D1 in the uterus and the increase was blocked by the antiestrogen ICI-182,780. When virgin female animals were fed a diet, that mimics exposure to either arsenite or cadmium, and challenged with the chemical carcinogen dimethylbenzanthracene, there was an increase in the incidence of mammary tumors and a decrease in the time to tumor onset, but no difference in the total number of tumors, tumor multiplicity, or total tumor volume. Together with published results, these data showed that environmentally relevant amounts of arsenite and cadmium had estrogen-like activity in vivo and promoted mammary tumorigenesis.
Topics: Animals; Arsenites; Benz(a)Anthracenes; Cadmium; Carcinogens; Cyclin D1; Estrogen Receptor alpha; Estrogens; Female; Humans; MCF-7 Cells; Mammary Glands, Human; Mammary Neoplasms, Animal; Neoplasm Proteins; Proto-Oncogene Proteins c-fos; Rats; Receptors, Progesterone
PubMed: 31646340
DOI: 10.1093/carcin/bgz176 -
BMC Complementary and Alternative... Sep 2019Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its...
BACKGROUND
Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved.
METHODS
Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 μL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 μL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin.
RESULTS
With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis.
CONCLUSIONS
Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Carcinogenesis; Carcinogens; Female; Furans; Kidney; Lactones; Liver; Mice; Mice, Inbred ICR; Signal Transduction; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate
PubMed: 31481122
DOI: 10.1186/s12906-019-2650-1 -
Nutrients Aug 2019Breast cancer and cardiovascular diseases (CVD) have shared risk factors and mechanisms of pathogenicity, as proven by increased cardiac risk in breast cancer patients...
Conjugated Linoleic Acid Isomers Affect Profile of Lipid Compounds and Intensity of Their Oxidation in Heart of Rats with Chemically-Induced Mammary Tumors-Preliminary Study.
Breast cancer and cardiovascular diseases (CVD) have shared risk factors and mechanisms of pathogenicity, as proven by increased cardiac risk in breast cancer patients receiving anticancerogenic therapies and in cancer survivors. A growing mammary tumor may cause heart injury in cancer patients who have not yet been treated. This study aimed to evaluate the effect of conjugated linoleic acid (CLA) supplementation of female rats with 7,12-dimethylbenz(a)anthracene (DMBA)-induced cancerogenesis on fatty acids (FAs), conjugated FAs (CFAs), malondialdehyde (MDA), cholesterol and oxysterols content in cardiac tissue. FAs, cholesterol and oxysterols contents were determined by gas chromatography coupled with mass spectrometry, while the contents of CFAs and MDA were determined by high performance liquid chromatography with photodiode detection. Our results indicate that both CLA supplementation and the presence of tumors influence the lipid biomarkers of CVD. A significant interaction of both experimental factors was observed in the content of polyunsaturated FAs (PUFAs), n-6 PUFAs and CFAs. CLA supplementation significantly inhibited PUFA oxidation, as evidenced by the lower content of MDA in rats' hearts, while the cancerous process intensified the oxidation of cholesterol, as confirmed by the elevated levels of 7-ketocholesterol in DMBA-treated rats. These results may significantly expand knowledge about CLA properties in terms of the prevention of co-existing non-communicable diseases.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Dietary Supplements; Female; Heart; Heart Diseases; Isomerism; Linoleic Acids, Conjugated; Lipid Peroxidation; Mammary Neoplasms, Experimental; Oxidation-Reduction; Rats
PubMed: 31480307
DOI: 10.3390/nu11092032 -
Breast Cancer Research : BCR Jul 2019Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain...
BACKGROUND
Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain biological characteristics, some of which may be clinically actionable, such as high immunogenicity. In mice, the medroxyprogesterone acetate (MPA) and 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumor model yields a heterogeneous set of tumors, a subset of which display claudin-low features. Neither the genomic characteristics of MPA/DMBA-induced claudin-low tumors nor those of human claudin-low breast tumors have been thoroughly explored.
METHODS
The transcriptomic characteristics and subtypes of MPA/DMBA-induced mouse mammary tumors were determined using gene expression microarrays. Somatic mutations and copy number aberrations in MPA/DMBA-induced tumors were identified from whole exome sequencing data. A publicly available dataset was queried to explore the genomic characteristics of human claudin-low breast cancer and to validate findings in the murine tumors.
RESULTS
Half of MPA/DMBA-induced tumors showed a claudin-low-like subtype. All tumors carried mutations in known driver genes. While the specific genes carrying mutations varied between tumors, there was a consistent mutational signature with an overweight of T>A transversions in TG dinucleotides. Most tumors carried copy number aberrations with a potential oncogenic driver effect. Overall, several genomic events were observed recurrently; however, none accurately delineated claudin-low-like tumors. Human claudin-low breast cancers carried a distinct set of genomic characteristics, in particular a relatively low burden of mutations and copy number aberrations. The gene expression characteristics of claudin-low-like MPA/DMBA-induced tumors accurately reflected those of human claudin-low tumors, including epithelial-mesenchymal transition phenotype, high level of immune activation, and low degree of differentiation. There was an elevated expression of the immunosuppressive genes PTGS2 (encoding COX-2) and CD274 (encoding PD-L1) in human and murine claudin-low tumors.
CONCLUSIONS
Our findings show that the claudin-low breast cancer subtype is not demarcated by specific genomic aberrations, but carries potentially targetable characteristics warranting further research.
Topics: Animals; Biopsy; Claudins; DNA Copy Number Variations; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Mammary Neoplasms, Animal; Mice; Mice, Transgenic; Mutation; Oncogenes; Transcriptome
PubMed: 31366361
DOI: 10.1186/s13058-019-1170-8 -
Molecular Carcinogenesis Aug 2019Substantial evidence suggests that 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis in mice mimics human breast cancer (BC) in many respects. Therefore,...
Substantial evidence suggests that 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis in mice mimics human breast cancer (BC) in many respects. Therefore, it has been used extensively to evaluate preventive and therapeutic agents for human BC. Mammary carcinogenesis induced by DMBA administration in female SENsitive to CARcinogen (SENCAR) mice was characterized by histopathological analysis of the mammary glands and alterations to the phosphatidylinositol 3-kinase/protein kinase B/cyclin-dependent kinase 1 (PI3K/Akt/CDK1) pathway. We recently reported that 2'-hydroxyflavanone (2HF) is a promising diet-derived chemotherapeutic agent that suppresses BC growth in vitro and in vivo by targeting a 76 kDa ral-interacting protein (RLIP). The objective of the current study was to investigate the synergistic anticarcinogenic effects of RLIP inhibition/depletion and 2HF in an in vivo model of DMBA-induced mammary carcinogenesis in SENCAR mice. Mice were given 2HF (50 mg/kg, bw, orally on alternate days), RLIP antibody (Rab; 5 mg/kg, bw, ip weekly), RLIP antisense (RAS; 5 mg/kg, b.w., ip weekly), or a combination of 2HF + Rab + RAS. Animals were monitored daily, and 7 days after the first appearance of moribund behavior, tissues were harvested for morphological and immunohistological analysis. Western blot analyses were performed to determine the expression of anti- and proapoptotic proteins in the mammary glands. Our results reveal that 2HF, RAS, and Rab significantly prevented the carcinogenic effects of DMBA administration in the mammary glands and other organs. Further, mice treated with a combination of 2HF + RAS + Rab exhibited no carcinogenic effect of DMBA as compared to either or the single agent-treated mice. This study demonstrates for the first time the anticarcinogenic effects of 2HF and RLIP inhibition/depletion in vivo in a novel DMBA-induced model of BC in SENCAR mice and provides the rationale for further clinical investigation.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; CDC2 Protein Kinase; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Flavanones; GTPase-Activating Proteins; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Inbred SENCAR; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 31006917
DOI: 10.1002/mc.23026 -
Experimental Animals Aug 2019Serous borderline ovarian tumors (SBOTs) behave between benign cystadenomas and carcinomas, and the effective detection and clinical management of SBOTs remain clinical...
Serous borderline ovarian tumors (SBOTs) behave between benign cystadenomas and carcinomas, and the effective detection and clinical management of SBOTs remain clinical challenges. Because it is difficult to isolate and enrich borderline tumor cells, a borderline animal model is in need. 7,12-dimethylbenz[a]anthracene (DMBA) is capable of inducing the initiation, promotion, and progression of serous ovarian tumors. This study aims to investigate the proper dosage and induction time of DMBA for rat models of SBOTs, and explore their morphological features demonstrated by magnetic resonance (MR) imaging and molecular genetic characteristics. Rats were randomly divided into six groups (1 mg/70 D, 2 mg/70 D, 3 mg/70 D, 2 mg/50 D, 2 mg/90 D, and 2 mg/110 D). The 3 mg/70 D group induced the most SBOTs (50.0%, 12/24). The micropapillary projections were shown on MR imaging, which was the characteristic of SBOTs. The Cyclin D1 characterizing an early pathogenetic event strongly expressed in induced serous benign tumors (SBTs). The immunoreactivity staining scores of P53 expression significantly increased from SBTs, SBOTs to serous ovarian carcinomas (SCAs), which elucidate that P53 might be a promising biomarker to grade serous ovarian tumors. Based on morphological and molecular genetic similarities, this rodent SBOT model was suitable for investigating the pathogenesis of serous ovarian tumors and developing an early detection strategy.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Ovarian Neoplasms; Random Allocation; Rats; Rats, Sprague-Dawley; Time Factors
PubMed: 30760660
DOI: 10.1538/expanim.18-0103