Dietary fat alters pulmonary metastasis of mammary cancers through cancer autonomous and non-autonomous changes in gene expression

Metastasis virulence, a significant contributor to breast cancer prognosis, is influenced by environmental factors like diet. We previously demonstrated in an F2 mouse population generated from a cross between the M16i polygenic obese and MMTV-PyMT mammary cancer models that high fat diet (HFD) decreases mammary cancer latency and increases pulmonary metastases compared to a matched control diet (MCD). Genetic analysis detected eight modifier loci for pulmonary metastasis, and diet significantly interacted with all eight loci. Here, gene expression microarray analysis was performed on mammary cancers from these mice. Despite the substantial dietary impact on metastasis and its interaction with metastasis modifiers, HFD significantly altered the expression of only five genes in mammary tumors; four of which, including serum amyloid A (Saa), are downstream of the tumor suppressor PTEN. Conversely, HFD altered the expression of 211 hepatic genes in a set of tumor free F2 control mice. Independent of diet, pulmonary metastasis virulence correlates with mammary tumor expression of genes involved in endocrine cancers, inflammation, angiogenesis, and invasion. The most significant virulence-associated network harbored genes also found in human adipose or mammary tissue, and contained upregulated Vegfa as a central node. Additionally, expression of Btn1a1, a gene physically located near a putative cis-acting eQTL on chromosome 13 and one of the metastasis modifiers, correlates with metastasis virulence. These data support the existence of diet-dependent and independent cancer modifier networks underlying differential susceptibility to mammary cancer metastasis and suggest that diet influences cancer metastasis virulence through tumor autonomous and non-autonomous mechanisms.     

Differential effect of hyperglycaemia on the immune response in an experimental model of diabetes in BALB/cByJ and C57Bl/6J mice: participation of oxidative stress

Diabetes is associated with an increased risk of death from infectious disease. Hyperglycaemia has been identified as the main factor contributing to the development of diseases associated with diabetes mellitus. However, experimental evidence indicates individual susceptibility to develop complications of diabetes. In this context, the aim of this work was to study the immune response in a streptozotocin‐induced type 1 diabetes in two mouse strains: BALB/cByJ and C57Bl/6J. The participation of hyperglycaemia and oxidative stress was also analysed. Diabetic BALB/cByJ mice showed a decrease in both the in‐vivo and in‐vitro immune responses, whereas diabetic C57Bl/6J mice had higher blood glucose but exhibited no impairment of the immune response. The influence of hyperglycaemia over the immune response was evaluated by preincubation of lymphocytes from normal mice in a high glucose‐containing medium. T and B cells from BALB/cByJ mice showed a decrease in cell viability and mitogen‐stimulated proliferation and an increase in apoptosis induction. An increase in oxidative stress was implicated in this deleterious effect. These parameters were not affected in the T and B lymphocytes from C57Bl/6J mice. In conclusion, BALB/cByJ mice were sensitive to the deleterious effect of hyperglycaemia, while C57BL/6J were resistant. Although an extrapolation of these results to clinical conditions must be handled with caution, these results highlight the need to contemplate the genetic background to establish models to study the deleterious effect of diabetes in order to understand phenotypical variations that are of clinical importance in the treatment of patients.     

Spontaneous metastasis in congenic mice with transgenic breast cancer is unaffected by plasminogen gene ablation

Plasminogen (Plg) plays a central role in tissue remodeling during ontogeny, development, and in pathological tissue remodeling following physical injury, inflammation and cancer. Plg/plasmin is, however, not critical for these processes, as they all occur to a varying extent in its absence, suggesting that there is a functional redundancy with other proteases. To explore this functional overlap in the transgenic MMTV-PyMT breast cancer metastasis model, we have combined Plg deficiency and a pharmacological metalloprotease inhibitor, which is known to reduce metastasis in this model, and has been shown to synergistically inhibit other tissue remodeling events in Plg-deficient mice. While metalloprotease inhibition dramatically reduced metastasis, we found no effect of Plg deficiency on metastasis, either independently or in combination with metalloprotease inhibition. We further show that Plg gene deficiency is of no significant consequence in this metastasis model, when analyzed in two different congenic strains: the FVB strain, and a F1 hybrid of the FVB and C57BL/6J strains. We suggest that the extensive backcrossing performed prior to our studies has eliminated the confounding effect of a known polymorphic metastasis modifier gene region located adjacent to the Plg gene.     

High expression of REGγ is associated with metastasis and poor prognosis of patients with breast cancer

REGgamma (REGγ) has been recently found in several types of human cancer, however, its clinical significance in metastasis and prognosis of breast cancer remains unknown. In this study, immunohistochemical staining and western blot analysis were performed to evaluate REGγ expression in both mouse and human breast cancer specimens. We found that in MMTV-PyMT mice, 14 out of 20 (70%) mouse mammary carcinomas were REGγ positive, which was significantly higher than control (0/20, 0%, P < 0.001) and lower than metastatic lung tumour (20/20, 100%, P = 0.027). Further investigation for REGγ expression in 136 human breast cancer tissues with the paired peritumoural normal breast tissues and 140 breast benign disease tissue samples showed that REGγ was undetectable in normal breast tissues and nonmetastatic axillary lymph nodes (ALNs), whereas 111 out of 136 (81.6%) breast cancer tissue samples were REGγ positive, which was significantly higher than breast benign disease tissues (9/140, 6.4%, P < 0.001) and lower than metastatic ALNs (116/116, 100%, P < 0.001). The 5-year disease-free and overall survivals of patients with negative/low level of REGγ were significantly higher than those of patients with high level of REGγ (P < 0.05). Cox regression analyses further indicated that REGγ could serve as a novel independent prognostic factor for breast cancer (OR = 4.369, P = 0.008). Our results suggest that the high expression of REGγ might predict metastasis and poor prognosis in breast cancer.     

Analyses of the role of endogenous SPARC in mouse models of prostate and breast cancer

Secreted protein, acidic and rich in cysteine (SPARC, also known as osteonectin or BM-40) is a glycoprotein component of the extracellular matrix that has been reported to be involved with a variety of cellular processes. Although SPARC expression levels are frequently altered in a variety of tumor types, the exact implications of deregulated SPARC expression—whether it promotes, inhibits or has no effect on tumor progression—have remained unclear. Our recent gene expression analyses have shown that SPARC is significantly downregulated in highly metastatic human prostate cancer cells. To test the role of endogenous SPARC in tumorigenesis directly, we examined cancer progression and metastasis in SPARC^+/− and SPARC^−/− mice using two separate transgenic mouse tumor models: transgenic adenocarcinoma of the mouse prostate (TRAMP) and murine mammary tumor virus-polyoma middle T (MMTV-PyMT). Surprisingly, in both instances, we found that loss of SPARC had no significant effects on tumor initiation, progression or metastasis. Tumor angiogenesis and collagen deposition were also largely unaffected. Our results indicate that, although differential SPARC expression may be a useful marker of aggressive, metastasis-prone tumors, loss of SPARC is not sufficient either to promote or to inhibit cancer progression in two spontaneous mouse tumor models.     

A New Model for Lymphatic Metastasis: Development of a Variant of the MDA-MB-468 Human Breast Cancer Cell Line that Aggressively Metastasizes to Lymph Nodes

Breast cancer often spreads from the primary tumor to regional lymph nodes. Lymph node status provides clinically important information for making treatment decisions. Spread via lymphatics is also important for the biology of breast cancer, as tumor cells in lymph nodes may provide a reservoir of cells leading to distant, lethal metastases. Improved understanding of the biology of lymphatic spread thus is important for improved breast cancer survival. Advances towards understanding the interactions between tumors cells and lymphatic vessels have in part been limited by the lack of suitable cell lines and experimental models. We have addressed this need by developing a new model of lymphatic metastasis. Here we describe the establishment of 468LN cells, a variant of the MDA-MB-468 human breast adenocarcinoma cell line, which produces extensive lymph node metastasis following orthotopic injection of nude mice. 468LN cells are also more aggressive in vitro, produce more osteopontin and express different surface integrins compared to the parent line. The dramatic in vitro and in vivo phenotypic and molecular differences of 468LN and parental 468GFP cells make this pair of cell lines a unique model for the specific study of lymph node metastasis of breast cancer.     

Elevated venous glutamate levels in (pre)catabolic conditions result at least partly from a decreased glutamate transport activity

Abnormally high postabsorptive venous plasma glutamate levels have been reported for several diseases that are associated with a loss of body cell mass including cancer, human/simian immunodeficiency virus infection, and amyotrophic lateral sklerosis. Studies on exchange rates in well-nourished cancer patients now show that high venous plasma glutamate levels may serve as a bona fide indicator for a decreased uptake of glutamate by the peripheral muscle tissue in the postabsorptive period and may be indicative for a precachectic state. High glutamate levels are also moderately correlated with a decreased uptake of glucose and ketone bodies. Relatively high venous glutamate levels have also been found in non-insulin-dependent diabetes mellitus and to some extent also in the cubital vein of normal elderly subjects, i.e., in conditions commonly associated with a decreased glucose tolerance and progressive loss of body cell mass.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus     

Diabetes‐induced Changes in Mannan‐binding Lectin Levels and Complement Activation in a Mouse Model of Type 1 Diabetes

Circulating mannan‐binding lectin (MBL) levels are elevated in type 1 diabetes. Further, high MBL levels are associated with the development of diabetic nephropathy. In animals, a direct effect of MBL on diabetic kidney changes is observed. We hypothesized that MBL levels and detrimental complement activation increase as a consequence of diabetes. We measured plasma MBL before and 7 weeks after inducing diabetes by streptozotocin. Mice have two MBLs, MBL‐A and MBL‐C. Diabetes induction led to an increase in MBL‐C concentration, whereas no change during the study was found in the control group. The increase in MBL‐C was associated with the increasing plasma glucose levels. In accordance with the observed changes in circulating MBL levels, liver expression of Mbl2mRNA (encoding MBL‐C) was increased in diabetes. Mbl1expression (encoding MBL‐A) did not differ between diabetic and control animals. The estimated half‐life of recombinant human MBL was significantly prolonged in mice with diabetes compared with control mice. Complement activation in plasma and glomeruli did not differ between groups. We demonstrate for the first time that MBL levels increase after induction of diabetes and in parallel with increasing plasma glucose. Our findings support the previous clinical observations of increased MBL in type 1 diabetes. This change may be explained by alternations in both MBL production and turnover.     

侧柏叶水煎液的降糖降脂作用

目的:研究侧柏叶(Platycladus orientalis)水煎液分别对高脂血症模型与糖尿病模型小鼠的降脂和降糖作用。方法:制备高脂血症小鼠模型,以体重升高率、肝指数、肝脏脂肪含量、血清总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)、脂联素(adiponectin,ADP)和白细胞介素6(interleukin-6,IL-6)含量以及动脉硬化指数(atherosclerosis index,AI)为指标,观察侧柏叶水煎液的降脂作用。制备糖尿病小鼠模型,以空腹血糖、糖耐量检测、血清肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)及胰岛素水平、胰岛素抵抗指数为指标,观察侧柏叶水煎液的降糖作用。结果:侧柏叶水煎液能明显降低高脂血症模型小鼠的体重增加率、肝指数、肝脏脂肪含量、AI以及血清TC、TG和IL-6水平(P0.05),升高血清ADP及HDL-C水平(P0.05),而且侧柏叶高剂量组对以上各指标的作用明显强于低剂量组。侧柏叶水煎液能明显减轻糖尿病模型小鼠糖耐量试验的异常,降低血清TNF-α和胰岛素水平,降低胰岛素抵抗系数(P0.05),且侧柏叶高剂量组效果强于低剂量组。结论:侧柏叶水煎液有明显的降脂降糖作用,且其作用具有剂量依赖性。其降脂作用的机制可能与其增加血清ADP及降低血清IL-6含量有关,而其降糖作用的机制可能与降低血清TNF-α水平有关。     

Characterization of breast cancers and therapy response by MRS and quantitative gene expression profiling in the choline pathway

Tumor choline metabolites have potential for use as diagnostic indicators of breast cancer phenotype and can be non‐invasively monitored in vivo by MRS. Extract studies have determined that the principle diagnostic component of these peaks is phosphocholine (PCho), the biosynthetic precursor to the membrane phospholipid, phosphatidylcholine (PtdCho). The ability to resolve and quantify PCho in vivo would improve the accuracy of this putative diagnostic tool. In addition, determining the biochemical mechanisms underlying these metabolic perturbations will improve the understanding of breast cancer and may suggest potential molecular targets for drug development. Reported herein is the in vivo resolution and quantification of PCho and glycerophosphocholine (GPC) in breast cancer xenografts in SCID mice via image‐guided ³¹P MRS, localized to a single voxel. Tumor metabolites are also detected using ex vivo extracts and high‐resolution NMR spectroscopy and are quantified in the metastatic tumor line, MDA‐mb‐231. Also reported is the quantification of cytosolic and lipid metabolites in breast cells of differing cancer phenotype, and the identification of metabolites that differ among these cell lines. In cell extracts, PCho and the PtdCho breakdown products, lysophosphatidylcholine, GPC and glycerol 3‐phosphate, are all raised in breast cancer lines relative to an immortalized non‐malignant line. These metabolic differences are in direct agreement with differences in expression of genes encoding enzymes in the choline metabolic pathway. Results of this study are consistent with previous studies, which have concluded that increased choline uptake, increased choline kinase activity, and increased phosholipase‐mediated turnover of PtdCho contribute to the observed increase in PCho in breast cancer. In addition, this study presents evidence suggesting a specific role for phospholipase A₂‐mediated PtdCho catabolism. Gene expression changes following taxane therapy are also reported and are consistent with previously reported changes in choline metabolites after the same therapy in the same tumor model. Copyright © 2008 John Wiley & Sons, Ltd.     

Tissue engineering a surrogate niche for metastatic cancer cells

In breast and prostate cancer patients, the bone marrow is a preferred site of metastasis. We hypothesized that we could use tissue-engineering strategies to lure metastasizing cancer cells to tissue-engineered bone marrow. First, we generated highly porous 3D silk scaffolds that were biocompatible and amenable to bone morphogenetic protein 2 functionalization. Control and functionalized silk scaffolds were subcutaneously implanted in mice and bone marrow development was followed. Only functionalized scaffolds developed cancellous bone and red bone marrow, which appeared as early as two weeks post-implantation and further developed over the 16-week study period. This tissue-engineered bone marrow microenvironment could be readily manipulated in situ to understand the biology of bone metastasis. To test the ability of functionalized scaffolds to serve as a surrogate niche for metastasis, human breast cancer cells were injected into the mammary fat pads of mice. The treatment of animals with scaffolds had no significant effect on primary tumor growth. However, extensive metastasis was observed in functionalized scaffolds, and the highest levels for scaffolds that were in situ manipulated with receptor activator of nuclear factor kappa-B ligand (RANKL). We also applied this tissue-engineered bone marrow model in a prostate cancer and experimental metastasis setting. In summary, we were able to use tissue-engineered bone marrow to serve as a target or “trap” for metastasizing cancer cells.     

BCG 免疫对2 型糖尿病小鼠血糖和免疫应答的影响

目的:探究BCG 免疫对2 型糖尿病小鼠血糖和免疫应答的影响。方法:BCG 经尾静脉注射小鼠,高糖高脂饮食联合小剂量多次腹腔注射链尿佐菌素建立2 型糖尿病模型。检测小鼠体重、空腹血糖和葡萄糖耐量试验血糖水平,测定小鼠细胞免疫应答水平。结果:BCG 免疫下调2 型糖尿病小鼠空腹血糖和糖负荷后的血糖水平;BCG 免疫促进Th1 型细胞反应,显著抑制2 型糖尿病小鼠Th2 型细胞因子的释放。结论:BCG 免疫可能通过抑制2 型糖尿病小鼠炎症因子的释放下调其血糖水平,有助于延缓糖尿病的发展进程。     

Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo

Obesity represents a risk factor for certain types of cancer. Leptin, a hormone predominantly produced by adipocytes, is elevated in the obese state. In the context of breast cancer, leptin derived from local adipocytes is present at high concentrations within the mammary gland. A direct physiological role of peripheral leptin action in the tumor microenvironment in vivo has not yet been examined. Here, we report that mice deficient in the peripheral leptin receptor, while harboring an intact central leptin signaling pathway, develop a fully mature ductal epithelium, a phenomenon not observed in db/db mice to date. In the context of the MMTV-PyMT mammary tumor model, the lack of peripheral leptin receptors attenuated tumor progression and metastasis through a reduction of the ERK1/2 and Jak2/STAT3 pathways. These are tumor cell-autonomous properties, independent of the metabolic state of the host. In the absence of leptin receptor signaling, the metabolic phenotype is less reliant on aerobic glycolysis and displays an enhanced capacity for β-oxidation, in contrast to nontransformed cells. Leptin receptor-free tumor cells display reduced STAT3 tyrosine phosphorylation on residue Y705 but have increased serine phosphorylation on residue S727, consistent with preserved mitochondrial function in the absence of the leptin receptor. Therefore, local leptin action within the mammary gland is a critical mediator, linking obesity and dysfunctional adipose tissue with aggressive tumor growth.     

Mutant <Emphasis Type="Italic">Bik</Emphasis> gene transferred by cationic liposome inhibits peritoneal disseminated murine colon cancer

Peritoneal carcinomatosis of intraabdominal malignancies, such as pancreatic, ovarian, gastric, and colorectal cancers, represents an unmet medical need as conventional cancer treatments rarely eliminate these tumors. Satisfactory treatment for either peritoneally disseminated tumors or prevention of local recurrence after surgery is yet to be developed. To improve the efficacy of novel strategies against peritoneal metastasis, a sensitive, and less invasive model is needed to scrutinize the in vivo tumor growth and response to experimental therapeutics. To study this we intraperitoneally inoculated CT-26 stably expressing luciferase (CT-26-Luc) to mimic tumor spreading within the abdomen. Bioluminescent signals emitted from the living experimental mice correlate well with the injected cell numbers as well as the weights of dissected tumors. Since a nonviral cationic liposome coupled mutant pro-apoptotic gene, Bik(T33D/S35D) (BikDD), was previously shown to have potent anti-cancer effects on an orthotopic breast cancer animal model (Li et al., Cancer Res 63(22):7630-7633, 2003), we evaluated the inhibitory effect of BikDD on the growth kinetics of intraperitoneally inoculated CT-26-Luc. We found that intraperitoneal (i.p.) injection of liposome coupled BikDD suppressed the expansion of CT-26-Luc and prolonged life span of experimental mice. These results suggest a therapeutic effect of BikDD gene therapy on peritoneal carcinomatosis of colon cancer.     

乳腺癌微环境成纤维细胞对乳腺癌细胞表达TIGAR 和Bcl-2 的影响

目的:探索乳腺癌微环境成纤维细胞对乳腺癌细胞表达TIGAR 和Bcl-2 的影响及对乳腺癌生长的作用。方法:体外实验,建立了人乳腺癌细胞株MDA-MB-231 和人成纤维细胞株CCC-ESF-1 共培养模型,RT-qPCR 和Western blot 检测成纤维细胞对乳腺癌细胞表达TIGAR 和Bcl-2 的影响,Annexin V 流式细胞术和Caspase-3 活性荧光检测乳腺癌细胞的凋亡;体内实验,建立人乳腺癌荷瘤裸鼠模型,测量荷瘤裸鼠肿瘤体积,免疫组化检测移植瘤组织TIGAR 和Bcl-2 的表达。结果:体外实验研究结果显示,共培养的成纤维细胞可上调MDA-MB-231 细胞TIGAR 和Bcl-2 的表达并抑制MDA-MB-231 细胞的凋亡;体内实验研究结果显示,与乳腺癌细胞共植入的成纤维细胞能上调荷瘤裸鼠乳腺癌组织TIGAR 和Bcl-2 的表达,高表达的TIGAR 和Bcl-2 可加速荷瘤裸鼠乳腺癌组织生长。结论:乳腺癌微环境成纤维细胞可上调乳腺癌细胞TIGAR 和Bcl-2 的表达,高表达的TIGAR 和Bcl-2 抑制乳腺癌细胞的凋亡,促进了乳腺癌的生长。     

Mutant C57Bl/KsLepr<Superscript>db/+</Superscript> mice as a genetic model of type 2 diabetes mellitus

The genetic model of diabetes mellitus was studied on mutant C57Bl/KsLepr^db/+ mice. These mice were characterized by high concentrations of glucose and glycosylated hemoglobin in the blood, polyuria, polyphagia, polydipsia, progressive obesity, biphasic morphological changes in insular islets of the pancreas (hyperplasia and atrophy), fatty degeneration of the liver, and hypoplasia of the spleen tissue and lymph nodes. Our results indicate that C57Bl/KsLepr^db/+ mice serve as an adequate model of type 2 diabetes mellitus. This model is suitable for testing of therapeutic methods for type 2 diabetes mellitus. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 12, pp. 664–667, December, 2007     

The thymus-dependent immune system in the pathogenesis of type 1 (insulin-dependent) diabetes mellitus. Animal model and human studies

The aim of the present study was to investigate the possible role of the thymus-dependent immune system in the disease mechanisms underlying type 1 (insulin-dependent) diabetes mellitus. Both animal experiments and human studies were carried out. Firstly, a brief historical review is given of the scientific progress within the aetiology and pathogenesis of diabetes mellitus during the last few decades. Mention is made summarily of some elements of the thymus-dependent immune system, and the athymic nude mouse is presented. Three diabetic animal models are reported, viz. two exogenously provoked diabetes models in mice, virus-induced diabetes and diabetes induced by streptozotocin, besides the spontaneously diabetic BB rat. Insofar as the mouse models are concerned, experiments were carried out on both nude mice and normal thymus-intact mice. Encephalomyocarditis virus was used in the virus model and could after inoculation be isolated in large quantities from nude mice as well as normal thymus-intact mice. Only the latter developed diabetes; the C57 mice in the form of glucose intolerance and the BALB/c/BOM mice in the form of elevation of the mean blood glucose values to about threefold normal level. The nude mice exhibited only a very short-lasting virus antibody formation, while in the thymus-intact mice it was possible, as might be expected, to demonstrate high titres of neutralizing virus antibodies for months after the virus inoculation. In the streptozotocin model, where the streptozotocin was administered by repeated small injections, the nude mice developed considerably milder diabetes than the thymus-intact mice. This survey includes other experiments using various forms of immunosuppression (thymectomy, irradiation, treatment with antilymphocyte serum), which together supply evidence that the thymus-dependent immune system is involved in the pathogenesis of diabetes in the two mouse models mentioned as well as in the spontaneously diabetic BB rat, regardless of the different aetiologies in the models. On this background, clinical immunological studies in patients with type 1 diabetes were carried out. Firstly, studies are reported of subpopulations of the peripheral lymphocytes which, after labelling with monoclonal antibodies, were investigated by means of flow-cytometry. The number of cytotoxic/suppressor T-lymphocytes was found to be reduced at the time of diagnosis of type 1 diabetes, but increasing towards normal levels five months later. The helper T-cells were found to be slightly increased at diagnosis as compared with the values in controls, whereas there were no differences in the total T-lymphocyte counts.(ABSTRACT TRUNCATED AT 400 WORDS)     

Paracrine overexpression of insulin-like growth factor-1 enhances mammary tumorigenesis in vivo

Insulin-like growth factor-1 (IGF-1) stimulates proliferation, regulates tissue development, protects against apoptosis, and promotes the malignant phenotype in the breast and other organs. Some epidemiological studies have linked high circulating levels of IGF-1 with an increased risk of breast cancer. To study the role of IGF-1 in mammary tumorigenesis in vivo, we used transgenic mice in which overexpression of IGF-1 is under the control of the bovine keratin 5 (BK5) promoter and is directed to either the myoepithelial or basal cells in a variety of organs, including the mammary gland. This model closely recapitulates the paracrine exposure of breast epithelium to stromal IGF-1 seen in women. Histologically, mammary glands from transgenic mice were hyperplastic and highly vascularized. Mammary glands from prepubertal transgenic mice had significantly increased ductal proliferation compared with wild-type tissues, although this difference was not maintained after puberty. Transgenic mice also had increased susceptibility to mammary carcinogenesis, and 74% of the BK5.IGF-1 mice treated with 7,12-dimethylbenz[a]anthracene (20 μg/day) developed mammary tumors compared with 29% of the wild-type mice. Interestingly, 31% of the vehicle-treated BK5.IGF-1 animals, but none of the wild-type animals, spontaneously developed mammary cancer. The mammary tumors were moderately differentiated adenocarcinomas that expressed functional, nuclear estrogen receptor at both the protein and mRNA levels. These data support the hypothesis that tissue overexpression of IGF-1 stimulates mammary tumorigenesis.     

Tissue-specific reduction of galanin content in the pancreas in alloxan diabetes in the mouse

Galanin inhibits insulin secretion and has been proposed to function as a sympathetic neurotransmitter in the endocrine pancreas in some species, for example in the dog. In this study, pancreatic and adrenal gland galanin content were measured following experimental diabetes induced by alloxan in mice. Three days after administration of alloxan (70mgkg^-1, i.p.) in normal mice, pancreatic content of galanin-like immunoreactivity (GLIR) was reduced to 65 ± 11 % of that in untreated controls (P < 0.01), whereas adrenal gland GLIR was unchanged. Similarly, 8 days after alloxan administration, pancreatic GLIR was reduced (P < 0.002), whereas adrenal gland GLIR was unaffected. Pancreatic GLIR also inversely correlated with plasma glucose levels (r = -0.5055, P < 0.005). To distinguish between the direct effects of alloxan vs. indirect metabolic effects induced by the drug, alloxan-diabetic mice were treated with insulin twice daily, which normalized the plasma glucose levels (7.6 ± 0.3 mmol l^-1). Pancreatic GLIR was then not significantly different from controls. Thus pancreatic but not adrenal gland GLIR content is reduced in alloxan-induced diabetes in mice. The data support a role for galanin as a pancreatic sympathetic neurotransmitter which may participate in the metabolic alterations seen in alloxan diabetes in mice.     

A Study on Hypoglycaemic Health Care Function of Stigma Maydis Polysaccharides

The objective of this paper was to study the therapeutic effect of Stigma maydis polysaccharides in diabetic mice. Mouse models of types 1 and 2 diabetes were established. The body weight, food intake, water intake as well as blood sugar level and glucose tolerance of mice were measured. Stigma maydis polysaccharides can improve the symptoms of weight loss and polydipsia in diabetic mice, and had an obvious antagonistic effect on alloxan-induced hyperglycaemia. The glucose tolerance test also showed that the Stigma maydis polysaccharides had very good effects on suppression and prevention of acute hyperglycaemia. Stigma maydis polysaccharides have some improvement effect on alloxan-induced types 1 and 2 diabetes.