Animal Models Of Colon Cancer Research Articles

Pathogenic conversion of RORγt+/Foxp3+ double positive regulatory T cells involves β-catenin up-regulation

Abstract The nature of regulatory T cells (Tregs) in cancer is ambivalent. In Colon Cancer (CC) patients and animal models of CC, we previously described a distinct subset of Tregs that suppresses anti-tumor effector T cell functions but simultaneously maintains inflammation. These Tregs co-express the Th17 lineage transcription factor RORγt along with Foxp3. Moreover, we causatively linked the pro-inflammatory skewing of T cells to Wnt/β-catenin-signaling. To elucidate how Wnt/β-catenin signaling orchestrates the induction of pathologic properties in Tregs we analyzed inflammatory bowel disease (IBD) patients. As IBD can progress to CC, this disease presents a unique platform to study the mechanisms underlying the emergence of RORγt+/Foxp3+Tregs. Indeed, in a sub-population of IBD patients we were able to detect RORγt+/Foxp3+Tregs, expressing high levels of β-catenin in the patients’ blood and tissue. To further establish that activated Wnt/β-catenin signaling is responsible for the pro-inflammatory skewing of Foxp3+ Tregs we over-expressed β-catenin Treg-specifically in a conditional Foxp3-Cre driven mouse model. Mice expressing constitutively active β-catenin in Tregs show striking X-linked immune pathology. Males die 4 weeks after birth of a severe scurfy-like phenotype. Although their Tregs are highly activated, they fail to suppress the proliferation of effector T cells. In heterozygous Foxp3-Cre mice, representing natural chimeras harboring wildtype and β-catenin over-expressing Tregs, the relative fitness of genetically altered Tregs is decreased. By further elucidating how Wnt/β-catenin signaling mediates the pathogenic conversion of Tregs, we hope to reveal novel targets for cancer immuno-therapy.

Early Prediction of Tumor Response to Bevacizumab Treatment in Murine Colon Cancer Models Using Three-Dimensional Dynamic Contrast-Enhanced Ultrasound Imaging

To evaluate whether three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) imaging allows assessing early changes in tumor perfusion following antiangiogenic treatment, and whether these changes could predict treatment response in two animal models of colon cancer that simulate clinical responders and nonresponders. Clinically responding (n=20; LS174T) and nonresponding (n=20; CT26) colon cancer xenografts were established in 40 mice. Ten mice from each group received either antiangiogenic therapy (anti-VEGF blocking with bevacizumab, 10mg/kg) or saline as controls and were imaged longitudinally with 3D DCE-US at baseline (day 0) and days 1, 3, 7, and 10 following treatment. The change in three perfusion parameters (peak enhancement [PE], area under curve [AUC], time to peak [TTP]) relative to baseline was compared to the percentage area of neovasculature on ex vivo quantitative immunofluorescence and with response at day 10 assessed by tumor volume. PE and AUC significantly decreased in LS174T tumors within 1 day after antiangiogenic treatment (P=0.005), but not in CT26 tumors (P>0.05). Similarly, the percentage area of neovasculature on immunofluorescence significantly decreased in treated vs. control LS174T tumors (P<0.001), but not in treated vs. control CT26 tumors (P=0.796). Early decrease in both PE and AUC by 45-50% were predictive of treatment response in 100% (95% CI, 69.2%, 100%) of responding tumors, and in 100% (95% CI, 88.4%, 100%) and 86.7% (95% CI, 69.3%, 96.2%), respectively, of nonresponding tumors. 3D DCE-US provides clinically relevant information on the variability of tumor response to antiangiogenic therapy and could eventually serve as a biomarker for predicting treatment outcomes.

The Effect of Sex on the Azoxymethane/Dextran Sulfate Sodium-treated Mice Model of Colon Cancer.

BackgroundThe colitis-associated cancer exhibits different characteristics according to sex in the initiation and progression of the tumors. The aim of this study was to investigate the sex-associated difference in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer model.MethodsThe AOM/DSS ICR mouse model was established to compare male with female, and then the severity of colitis-associated carcinogenesis was examined macroscopically and histologically regarding the number, size, and location of tumors. Subsequently, levels of colonic mucosal cytokine, interleukin (IL)-1β and myeloperoxidase (MPO) were assessed.ResultsAt the 16th week, the tumor multiplicity and the pro-inflammatory factors differed according to sex. The total tumor number was significantly higher in male (P = 0.020) and the number of large tumors (diameter > 2 mm) was higher in male (P = 0.026). In male, the tumors located more in distal colon (P = 0.001). MPO was significantly higher in AOM/DSS-treated male mice compared to the control group (P = 0.003), whereas the corresponding female group showed no significant change (P = 0.086). Colonic IL-1β level significantly increased in AOM/DSS groups compared to control groups both in male and female (male, P = 0.014; female, P = 0.005). It was higher in male group; however, there was no statistical significance (P = 0.226).ConclusionsIn AOM/DSS murine model, colitis-associated colon tumorigenesis are induced more severely in male mice than female probably by way of inflammatory mediators such as IL-1β and MPO. The sex-related differences at the animal model of colon cancer suggest the importance of approach to disease with sex-specific medicine in human.

The Interaction between Dietary Fiber and Fat and Risk of Colorectal Cancer in the Women's Health Initiative.

Combined intakes of specific dietary fiber and fat subtypes protect against colon cancer in animal models. We evaluated associations between self-reported individual and combinations of fiber (insoluble, soluble, and pectins, specifically) and fat (omega-6, omega-3, and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), specifically) and colorectal cancer (CRC) risk in the Women’s Health Initiative prospective cohort (n = 134,017). During a mean 11.7 years (1993–2010), 1952 incident CRC cases were identified. Cox regression models computed multivariate adjusted hazard ratios to estimate the association between dietary factors and CRC risk. Assessing fiber and fat individually, there was a modest trend for lower CRC risk with increasing intakes of total and insoluble fiber (p-trend 0.09 and 0.08). An interaction (p = 0.01) was observed between soluble fiber and DHA + EPA, with protective effects of DHA + EPA with lower intakes of soluble fiber and an attenuation at higher intakes, however this association was no longer significant after correction for multiple testing. These results suggest a modest protective effect of higher fiber intake on CRC risk, but not in combination with dietary fat subtypes. Given the robust results in preclinical models and mixed results in observational studies, controlled dietary interventions with standardized intakes are needed to better understand the interaction of specific fat and fiber subtypes on colon biology and ultimately CRC susceptibility in humans.

Ultrasound imaging of splenomegaly as a proxy to monitor colon tumor development in Apc(min716/+) mice.

Animal models of colon cancer are widely used to understand the molecular mechanisms and pathogenesis of the disease. These animal models require a substantial investment of time and traditionally necessitate the killing of the animal to measure the tumor progression. Several in vivo imaging techniques are being used in both human clinics and preclinical studies, albeit at high cost and requiring particular expertise. Here, we report that the progression of splenomegaly coincides with and positively correlates to colon tumor development in Apc min716/+ mice expressing a mutant gene encoding an adenomatous polyposis coli protein truncated at amino acid 716. Ultrasound image‐based spleen size measurement precisely mirrors splenomegaly development in vivo in the tumor‐laden Apc min716/+ mice. Moreover, the spleen dimensions extracted from the ultrasound sonograms are positively correlated with normalized spleen weight and the number and area of colon tumors. Hence, we propose measuring the spleen size in vivo by ultrasound imaging as a novel approach to estimate splenomegaly development and to indirectly monitor colon tumor development in Apc min716/+ mice. The widespread use of ultrasound machines in the laboratory setting, coupled with the fact that it is a noninvasive method, make it a straightforward and useful tool for monitoring the experimental progress of colon cancer in mice and determining end points without killing animals strictly for diagnostics purposes.

Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression

ABSTRACTMethylglyoxal (MG) is a highly reactive dicarbonyl compound exhibiting anti-tumor activity. The anti-tumor effects of MG have been demonstrated in some types of cancer, but its role in colon cancer and the mechanisms underlying this activity remain largely unknown. We investigated its role in human colon cancer and the underlying mechanism using human colon cancer cells and animal model. Viability, proliferation, and apoptosis were quantified in DLD-1 and SW480 colon cancer cells by using the Cell Counting Kit-8, plate colony formation assay, and flow cytometry, respectively. Cell migration and invasion were assessed by wound healing and transwell assays. Glucose consumption, lactate production, and intracellular ATP production also were assayed. The levels of c-Myc protein and mRNA were quantitated by western blot and qRT-PCR. The anti-tumor role of MG in vivo was investigated in a DLD-1 xenograft tumor model in nude mice. We demonstrated that MG inhibited viability, proliferation, migration, and invasion and induced apoptosis of DLD-1 and SW480 colon cancer cells. Treatment with MG reduced glucose consumption, lactate production, and ATP production and decreased c-Myc protein levels in these cells. Moreover, MG significantly suppressed tumor growth and c-Myc expression in vivo. Our findings suggest that MG plays an anti-tumor role in colon cancer. It inhibits cancer cell growth by altering the glycolytic pathway associated with downregulation of c-Myc protein. MG has therapeutic potential in colon cancer by interrupting cancer metabolism.

P-201 A Comparative Study for Effectiveness of Irreversible Electroporation Ablation according to Therapeutic Method: Colon Cancer Animal Model

P-201 A Comparative Study for Effectiveness of Irreversible Electroporation Ablation according to Therapeutic Method: Colon Cancer Animal Model

Honey and its Phytochemicals: Plausible Agents in Combating Colon Cancer through its Diversified Actions

Cancer is one of the leading causes of death worldwide. Among them, colorectal cancer is linked with diet as the epithelial cells of colon and rectum come in direct contact with diet. Diets rich in phenolic constituents are associated in eradicating various noncommunicable diseases including cancer. This work illustrates antiproliferative effects of honey and its phytochemicals against colorectal cancer to limelight. Honey and its phytochemicals are found to inhibit the cancer growth. Changes like activation of caspase-3, caspase-8, polyadenosine diphosphate-ribose polymerase cleavage, boost in ROS level activating mitochondrial pathway, lipid layer breakage, DNA fragmentation, increase of G0/G1 phase cells, up-regulation of Bax regulators and p53 dependent apoptosis are significant. It is high time for scientists to initiate more trails using honey and its phytochemicals against some immune-deficient animal models of colon cancer and in low- and high-risk human individuals to validate honey as a mighty sword against colon cancer. This review promulgates honey and its phytochemicals as candidates in colon cancer prevention. Practical Application: Colon cancer is the third largest cause of cancer death worldwide. The standard chemotherapeutic agents are usually noneffective in the latter stages of cancer. As colorectal cancer is more prone to the diet consumed, scientists have explored many dietary compounds to treat this particular type of cancer. In our review, we highlight the effect of honey and its phenolic constituents against the colon cancer cells. Various, in vitro experiments done are enlisted. This review also emphasis the need of numerous studies that are needed to be initiated to explore the anticancer effect of crude honey specifically. As honey is one of the ingredients used in daily life, honey can also be used in chemoprevention against colon cancer.

Near-Infrared Fluorescence Endoscopy to Detect Dysplastic Lesions in the Mouse Colon.

Near-infrared fluorescence (NIRF) endoscopy has a great potential for efficient early detection of dysplastic lesions in the colon. For preclinical studies, we developed a small animal NIRF endoscope and successfully used this device to identify dysplastic lesions in a murine model of chronic colitis. In this chapter, we present a step-by-step protocol for using NIRF endoscopy to examine the location, the size, and the borders of the dysplastic lesions developed in murine colitis. Our studies suggest that NIRF endoscopy is a specific and sensitive technique that provides a unique opportunity to analyze early stages of tumorigenesis in animal models of colon cancer and to perform surveillance colonoscopy in patients with colitis-associated colon cancer.

Extract of the Bark of Bathysa cuspidataAttenuates the Development of Chemically-Induced Preneoplastic Colorectal Lesions in Rats

The aim of this study was to investigate the effect of the bark extractBathysa cuspidata on chemically induced preneoplastic colorectal lesions in Wistar rats. Forty male rats were randomly divided into four groups (n = 10 each): saline (control group, oral administration of saline solution 0.9%); dimethylsulfoxide (DMSO, vehicle control), B200 (treated with 200 mg/kg bark extract ofB. cuspidata), and B400 (treated with 400 mg/kg bark extract ofB. cuspidata). Administration of treatments was carried out by the gavage. The animals received four subcutaneous injections of 1,2-dimethylhydrazine (DMH, 40 mg/kg) in the initial two weeks of the experiment to induce preneoplastic colorectal lesions. After 15 weeks, the animals were euthanized and the presence of aberrant crypt foci (ACF), body weight, biochemical analyses, and oxidative stress markers were measured. The extract ofB. cuspidata decreased the levels of superoxide dismutase (SOD), but did not influence the levels of catalase (CAT), malondialdehyde (MDA), nitric oxide or protein carbonyl, compared with the saline group. The animals supplemented with a more concentratedB. cuspidata extract (B400) showed a significant reduction in the number of ACF in all the portions of the intestinal mucosa. The study demonstrated that the bark extract ofB. cuspidata at 400 mg/kg reduced the preneoplastic colorectal lesions in an animal model of colon cancer and that the effect could be dose-dependent.

ID: 13: The biology of Interleukin-6 and strategies of blockade

Cytokines receptors exist in membrane bound and soluble form. The IL-6/soluble IL-6R complex stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process ’trans-signaling’. The soluble IL-6R is generated via ectodomain shedding by the membrane bound metalloprotease ADAM17. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses. The dimerized recombinant soluble gp130Fc fusion protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. Interestingly, depending on the animal model used, global blockade of IL-6 signaling by neutralizing monoclonal antibodies and selective blockade of IL-6 trans-signaling can lead to different consequences. We used neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling in several animal models of human diseases. Inhibition of IL-6 trans-signaling but not global IL-6 blockade was beneficial in the cecal ligation and puncture sepsis model. Defense against bacterial infections rely on the membrane bound IL-6R. Acute pancreatitis often results in subsequent acute lung injury, which is an inflammatory disease with high mortality. IL-6 is necessary for the inflammatory process to reach the lung and blockade of IL-6 trans-signaling is sufficient to block the disease. The extent of inflammation is controlled by trans-signaling via the soluble IL-6R. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in animal models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis, pancreatitis, lupus erythematodes, colon cancer, ovarian cancer, pancreatic cancer, nephrotoxic nephritis and high fat diet induced obesity that IL-6 trans-signaling via the soluble IL-6R is the crucial step in the development and the progression of the disease. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer and it underwent phase I clinical trials as an anti-inflammatory in 2013/2014. Phase II clinical trials in patients with autoimmune diseases such as inflammatory bowel disease will follow in 2015/16.

An anti-EpCAM antibody EpAb2-6 for the treatment of colon cancer.

Epithelial cell adhesion molecule (EpCAM) is known to be overexpressed in epithelial cancers associated with enhanced malignant potential, particularly colorectal carcinoma (CRC) and head and neck squamous cell carcinoma (HNSCC). However, it is unknown whether progression of malignance can be directly inhibited by targeting EpCAM. Here, we have generated five novel monoclonal antibodies (mAbs) against EpCAM. One of these anti-EpCAM mAbs, EpAb2-6, was found to induce cancer cell apoptosis in vitro, inhibit tumor growth, and prolong the overall survival of both a pancreatic cancer metastatic mouse model and mice with human colon carcinoma xenografts. EpAb2-6 also increases the therapeutic efficacy of irinotecan, fluorouracil, and leucovorin (IFL) therapy in a colon cancer animal model and gemcitabine therapy in a pancreatic cancer animal model. Furthermore, EpAb2-6, which binds to positions Y95 and D96 of the EGF-II/TY domain of EpCAM, inhibits production of EpICD, thereby decreasing its translocation and subsequent signal activation. Collectively, our results indicate that the novel anti-EpCAM mAb can potentially be used for cancer-targeted therapy.

P-208 The Therapeutic Effect of Irreversible Electroporation Ablation in Colon Cancer Animal Model

P-208 The Therapeutic Effect of Irreversible Electroporation Ablation in Colon Cancer Animal Model

Sa1596 The Therapeutic Effect of Irreversible Electroporation Ablation in Colon Cancer Animal Model

Irreversible electroporation (IRE) is a promising novel technique for the ablation of tumors. IRE has an advantage over other ablation technique in its mechanism to remove undesired cells by affecting the cell membrane without thermally destructing blood vessels, nerves and the surrounding tissues. Studies regarding the clinical application of IRE have been performed in humans, as well as in animals, for organs such as the liver, kidney, prostate, etc. and IRE is now accepted as a novel anti-cancer ablation modality.

New insights from animal models of colon cancer: inflammation control as a new facet on the tumor suppressor APC gem

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide. As with other cancers, CRC is a genetic disease, however, several risk factors including diet and chronic colitis predispose to the disease. Mutations in the tumor suppressor adenomatous polyposis coli (APC) initiate most cases of CRC. Recent data from mouse models suggest that APC mutations and colitis are not completely independent factors in colorectal carcinogenesis. Here, we review the evidence supporting an interaction between APC muta- tions and chronic colitis. We will also discuss possible pathophysiologic mechanisms behind this interaction.

Diallyl Disulphide Protects against Colon Cancer in vitro, of HT-29 Cells and in Male Rabbits of Colon Cancer Model: An Analysis of Genetic and Epigenetic Variations

Diet and dietary habits are currently accused of being among cancer causing agents. The present study was carried out in a trial to point at the beneficial anti-cancer properties of one the most Egyptian traditional food components (Garlic). We studied the anti-cancerous properties of Diallyl disulphide (DADS), a major organosulfur compound in garlic oil, on HT29 colon cancer cell line and in vivo of male rabbits (Oryctolagus cuniculus) as an animal model of colon cancer. DADS showed differential effect on the expression of a group of genes, as it down-regulated the expression of oncogenes (e.g., CTNNB1, CCDN1, BIRC5, MYC and AKT), while up-regulated the expression of tumour suppressor gene (TP53) and apoptosis regulator gene (BAX). DADS apoptotic effect was also seen via inducing the expression of cytochrome c and activation of caspase-3. Moreover, DADS induced chromatin configuration changes through increasing histone acetylation of histone-3 and -4. Examination of 1,2 dimethyl hydrazine (DMH) induced cancer in vivo model (O. cuniculus) showed histological changes characteristic for colon tumorigenesis such as, hyperplastic intraepithelial lesions, neoplastic changes and lymphocytes infiltration, which were strongly attenuated in animals coinjected with both DADS and DMH and were not observed in the animals that received DADS prior to DMH treatment. This study suggested the protective properties of DADS against colon cancer in vitro and in vivo.

DAC can restore expression of NALP1 to suppress tumor growth in colon cancer.

Despite recent progress in the identification of genetic and molecular alternations in colorectal carcinoma, the precise molecular pathogenesis remains unclear. NALP1 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 1) is a member of the nucleotide-binding oligomerization domain-like receptor family of proteins that are key organization proteins in the inflammasome. It is reported that NALP1 plays a central role in cell apoptosis, pyroptosis, inflammatory reactions and autoimmune diseases. DAC (5-aza-2-deoxycytidine) is an antitumor drug useful to lung cancer, myelodysplastic disorders, myelodysplasia and acute myeloid leukemia. In this study, we examined the expression of NALP1 in human normal and cancerous colon tissues using tissue microarray, western blot and quantitative real-time PCR and we measured the expression of NALP1 in three kinds of colon cancer cell lines and animal models before and after treatment with DAC. Furthermore, we examined the treatment effects of DAC on colon cancer in our animal model. Our data indicate that NALP1 is expressed low in human colorectal tumoral tissues relative to paratumoral tissues and was associated with the survival and tumor metastasis of patients. The expression of NALP1 increased after treatment with DAC both in vitro and in vivo. Furthermore, DAC suppressed the growth of colon cancer and increased lifespan in mouse model. Therefore, we conclude that NALP1 is expressed low in colon cancer and associated with the survival and tumor metastasis of patients, and treatment with DAC can restore NALP1 levels to suppress the growth of colon cancer.

Suppression of mucin 2 promotes interleukin-6 secretion and tumor growth in an orthotopic immune-competent colon cancer animal model.

Mucin 2 (MUC2) is the major secreted mucin of the large intestine and is expressed by adenomas and mucinous carcinomas. Since colon cancer is associated with a proinflammatory microenvironment and dysregulated MUC2 expression, the aim of this study was to characterize the effects of MUC2 gene expression in colon tumor progression using colonic cancer cells. CT26 colon cancer cells were stably transfected with MUC2 siRNA (MUC2 RNAi) or a control construct containing a nonspecific sequence (scrambled RNAi). Expression of MUC2 was significantly decreased in the MUC2 RNAi cell clones. Although MUC2 suppression did not affect the cell growth of colon cancer cells in vitro, MUC2 knockdown promoted tumor growth in an orthotopic colon cancer model in vivo. MUC2 silencing also increased interleukin (IL)-6 secretion by colon cancer cells. IL-6 neutralization attenuated tumor formation by MUC2 RNAi cells; it also increased CD8 T cell infiltration into the peritoneum. Taken together, to the best of our knowledge, this is the first study indicating that the immune response to cancer cells plays an important role in tumor growth regulated by MUC2. Furthermore, given the effects of MUC2 on IL-6 secretion, its targeting may represent a potentially useful strategy to treat colonic carcinomas.

S-21 : Blocking only the bad side of Interleukin-6

Cytokines receptors exist in membrane bound and soluble form. The IL-6/soluble IL-6R complex stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process ‘ trans-signaling ’. The soluble IL-6R is generated via ectodomain shedding by the membrane bound metalloprotease ADAM17. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses [1] . The dimerized recombinant soluble gp130Fc fusion protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. Interestingly, depending on the animal model used, global blockade of IL-6 signaling by neutralizing monoclonal antibodies and selective blockade of IL-6 trans-signaling can lead to different consequences. We used neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling in several animal models of human diseases. Inhibition of IL-6 trans-signaling but not global IL-6 blockade was beneficial in the cecal ligation and puncture sepsis model [2] . Defense against bacterial infections rely on the membrane bound IL-6R [3] . Acute pancreatitis often results in subsequent acute lung injury, which is an inflammatory disease with high mortality. IL-6 is necessary for the inflammatory process to reach the lung and blockade of IL-6 trans-signaling is sufficient to block the disease [4] . The extent of inflammation is controlled by trans-signaling via the soluble IL-6R. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in animal models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis, pancreatitis, lupus erythematodes, colon cancer, ovarian cancer and pancreatic cancer that IL-6 trans-signaling via the soluble IL-6R is the crucial step in the development and the progression of the disease [1] , [2] , [3] , [4] , [5] . Therefore, sgp130Fc is a novel therapeutic agent for treatment of chronic inflammatory diseases and cancer and it underwent phase I clinical trials as an anti-inflammatory in 2013/2014. Phase II clinical trials in patients with autoimmune diseases such as inflammatory bowel disease will follow next year.

Hypothalamic Gene Transfer of BDNF Inhibits Breast Cancer Progression and Metastasis in Middle Age Obese Mice

Activation of the hypothalamus-adipocyte axis is associated with an antiobesity and anticancer phenotype in animal models of melanoma and colon cancer. Brain-derived neurotrophic factor (BDNF) is a key mediator in the hypothalamus leading to preferential sympathoneural activation of adipose tissue and the ensuing resistance to obesity and cancer. Here, we generated middle age obese mice by high fat diet feeding for a year and investigated the effects of hypothalamic gene transfer of BDNF on a hormone receptor-positive mammary tumor model. The recombinant adeno-associated viral vector-mediated overexpression of BDNF led to marked weight loss and decrease of adiposity without change of food intake. BDNF gene therapy improved glucose tolerance, alleviated steatosis, reduced leptin level, inhibited mouse breast cancer EO771 growth, and prevented the metastasis. The reduced tumor growth in BDNF-treated mice was associated with reduced angiogenesis, decreased proliferation, increased apoptosis, and reduced adipocyte recruitment and lipid accumulation. Moreover, BDNF gene therapy reduced inflammation markers in the hypothalamus, the mammary gland, the subcutaneous fat, and the mammary tumor. Our results suggest that manipulating a single gene in the brain may influence multiple mechanisms implicated in obesity-cancer association and provide a target for the prevention and treatment of both obesity and cancer.