Quercus spp. extract as a promising preventive or therapeutic strategy for cancer: A systematic review.

Acorns have traditionally been used in the human diet and for the treatment of specific diseases. Therefore, the present study performed a systematic review of studies which investigated the effects of Quercus spp. extracts in cancer prevention and treatment. A systematic literature search was performed for original records which addressed the anticancer effects of Quercus spp. extract in in vitro and in vivo cancer models. Body composition, food consumption, tumor development and/or toxicity were evaluated in in vivo studies, while cytotoxicity was evaluated in in vitro studies. Few studies and low sample sizes presented a challenge in the drawing of solid conclusions. Overall, the results suggested a positive impact of Quercus spp. extract, by reducing cancer development. Therefore, more studies with different cancer cell lines and animal models to address the efficacy of the acorn extracts in several types of cancer are required. Furthermore, the effects of acorn flour, incorporated in the diet, in an animal model of mammary cancer should be evaluated.

Toxicological and anti-tumor effects of a linden extract (Tilia platyphyllos Scop.) in a HPV16-transgenic mouse model.

Tilia platyphyllos Scop. is a popular broad-leaved tree, native to Central and Southern Europe. Hydroethanolic extracts rich in phenolic compounds obtained from T. platyphyllos Scop. have shown in vitro antioxidant, anti-inflammatory and antitumor properties. The aim of this work was to evaluate the therapeutic properties of a hydroethanolic extract obtained from T. platyphyllos in HPV16-transgenic mice. The animals were divided into eight groups according to their sex and phenotype. Four groups of female: HPV+ exposed to linden (HPV linden; n = 6), HPV+ (HPV water; n = 4), HPV- exposed to linden (WT linden; n = 5) and HPV- (WT water; n = 4) and four groups of male: HPV+ exposed to linden (HPV linden; n = 5), HPV+ (HPV water; n = 5), HPV- exposed to linden (WT linden; n = 5) and HPV- (WT water; n = 7). The linden (Tilia platyphyllos Scop.) extract was orally administered at a dose of 4.5 mg/10 mL per animal (dissolved in water) and changed daily for 33 days. The hydroethanolic extract of T. platyphyllos consisted of protocatechuic acid and (-)-epicatechin as the most abundant phenolic acid and flavonoid, respectively, and was found to be stable during the studied period. In two male groups a significant positive weight gain was observed but without association with the linden extract. Histological, biochemical, and oxidative stress analyses for the evaluation of kidney and liver damage support the hypothesis that the linden extract is safe and well-tolerated under the present experimental conditions. Skin histopathology does not demonstrate the chemopreventive effect of the linden extract against HPV16-induced lesions. The linden extract has revealed a favourable toxicological profile; however, additional studies are required to determine the chemopreventive potential of the linden extract.

Effects of exercise training on breast cancer metastasis in a rat model.

Exercise training is thought to play a protective role against cancer development and metastasis, either by reducing hormonal stimulation of hormone-dependent cancers or by reducing the permeability of vascular walls towards invading metastatic cells. The purpose of this work was to evaluate the role of long-term exercise training in the development and metastasis of breast cancer, in an immune-competent 1-methyl-1-nitrosourea (MNU) induced rat model. A single MNU dose was administered to Sprague-Dawley rats at 50 days of age and the rats were subjected to exercise training on a treadmill at 20 m/min, 60 min/day, 5 days/week for 35 weeks. Exercised animals developed slightly less (2.30 ± 1.42) tumours per animal than sedentary animals (2.55 ± 1.44) and did not develop any metastasis, while two pulmonary metastases were observed in the sedentary group. All primary neoplasms and their metastases were positive for oestrogen (ER) α and progesterone (PR) receptors, indicating high hormonal sensitivity. Interestingly, exercise training increased circulating oestrogen levels, thus suggesting that the mechanism might involve either or both of a protective hormone-independent effect and modulation of tumoural vascularization.

Prognostic factors in MNU and DMBA-induced mammary tumors in female rats.

Chemically-induced mammary tumors in rats by the carcinogens 1-methyl-1-nitrosourea- (MNU) and 7,12-dimethylbenz[a]anthracene (DMBA) are the most widely used models for studies related with human breast cancer. This study aimed to evaluate the immunoexpression of the prognostic factors estrogen receptor α (ERα), progesterone receptor (PR) and Ki-67, in MNU and DMBA-induced rat mammary tumors, in order to know the model that best suits to woman breast cancer. Twenty-eight MNU-induced and 16 DMBA-induced mammary tumors in virgin female Sprague-Dawley rats were analyzed. The expression of the prognostic markers ERα, PR and Ki-67 proliferation index (Ki-67 PI) was assessed by immunohistochemistry. Mitotic activity index (MAI) was also evaluated. More than one histological pattern was identified in each mammary tumor. Carcinomas constituted the lesions most frequently induced by both carcinogens: 33 MNU-induced carcinomas and 23 DMBA-induced carcinomas. All MNU and DMBA-induced mammary carcinomas were ER+/PR+, with a higher expression of ERα when compared with PR. Tumors' weight, the expression of ERα, PR, Ki-67 PI and MAI were higher in MNU-induced mammary carcinomas when compared with the DMBA-induced ones. Statistically significant differences between groups were observed for ERα, PR and MAI (p<0.05). The higher KI-67 PI and MAI in MNU-induced mammary carcinomas are suggestive of a higher aggressiveness of these carcinomas when compared with the DMBA-induced ones, and consequently a worse response to the therapy and a worse prognosis. In this way, the use of the rat model of MNU-induced mammary tumors is advised in experimental protocols aiming to study more aggressive mammary tumors within the group of double-positive mammary tumors (ER+/PR+).

Experimental mammary carcinogenesis - Rat models.

Mammary cancer is one of the most common cancers, victimizing more than half a million of women worldwide every year. Despite all the studies in this field, the current therapeutic approaches are not effective and have several devastating effects for patients. In this way, the need to better understand the mammary cancer biopathology and find effective therapies led to the development of several rodent models over years. With this review, the authors intended to provide the readers with an overview of the rat models used to study mammary carcinogenesis, with a special emphasis on chemically-induced models.

A spontaneous high-grade undifferentiated mammary carcinoma in a seven-week-old female rat.

The present work describes a rare case of a spontaneous high-grade carcinoma in a seven-week-old Sprague-Dawley female rat that had been included in the control group of an assay of mammary carcinogenesis. The mass was detected at 50days of age, it grown quickly and the animal was humanely sacrificed eight days later. The tumor was located in the left cervical region, in the vicinity of the left submandibular and sublingual glands. It was soft and reddish and had several dens with a bloody content. The tumor was PAS negative and exhibited immunostaining for ER-α. The histopathologic and immunohistochemical data are suggestive of a high-grade carcinoma from mammary gland. It was the first report of a spontaneous mammary tumor in such a young rat.

Effects of lifelong exercise training on mammary tumorigenesis induced by MNU in female Sprague-Dawley rats.

Breast cancer is the most common malignancy in women worldwide. Several studies have suggested that exercise training may decrease the risk of breast cancer development. This study aimed to evaluate the effects of long-term exercise training on mammary tumorigenesis in an animal model of mammary cancer. Fifty female Sprague-Dawley rats were randomly divided into four groups: MNU sedentary, MNU exercised, control sedentary and control exercised. Animals from MNU groups received an intraperitoneal administration of N-methyl-N-nitrosourea (MNU). Animals were exercised on a treadmill during 35 weeks. When animals were killed, blood samples were collected to determine the hematocrit and to perform the biochemical analysis. Mammary tumors were collected and histologically evaluated; the expression of ERs α and ß was evaluated in tumor sections by immunohistochemistry. All survived animals from both MNU groups developed mammary tumors. The number of mammary tumors (p > 0.05) and lesions (p = 0.056) was lower in MNU exercised than in MNU sedentary animals. MNU exercised animals showed lower number of malignant lesions than MNU sedentary animals (p = 0.020). C-reactive protein serum concentration was lower in exercised animals; however, the levels of 17-ß estradiol were higher in exercised animals. Tumors from exercised animals exhibited higher expression of ER α than tumors from sedentary animals (p < 0.05). This study analyzes the impact of the longest exercise training protocol on mammary tumorigenesis ever performed. We concluded that the lifelong endurance training has beneficial effects on mammary tumorigenesis in female rats (reduced the inflammation, the number of mammary tumors and lesions, and histological grade of malignancy). Additionally, the mammary tumors from MNU exercised group exhibited higher immunoexpression of ER α that is an indicator of well-differentiated tumors and better response to hormone therapy.

HPV16 induces a wasting syndrome in transgenic mice: Amelioration by dietary polyphenols via NF-κB inhibition.

Cancer patients often show a wasting syndrome for which there are little therapeutic options. Dietary polyphenols have been proposed for treating this syndrome, but their usefulness in cases associated with human papillomavirus (HPV)-induced cancers is unknown. We characterized HPV16-transgenic mice as a model of cancer cachexia and tested the efficacy of long-term oral supplementation with polyphenols curcumin and rutin. Both compounds were orally administered to six weeks-old HPV16-transgenic mice showing characteristic multi-step skin carcinogenesis, for 24weeks. Skin lesions and blood, liver and spleen inflammatory changes were characterized histologically and hematologically. Hepatic oxidative stress, skeletal muscle mass and the levels of muscle pro-inflammatory transcription factor NF-κB were also assessed. Skin carcinogenesis was associated with progressive, severe, systemic inflammation (leukocytosis, hepatitis, splenitis), significant mortality and cachexia. Curcumin and rutin totally suppressed mortality while reducing white blood cells and the incidence of splenitis and hepatitis. Rutin prevented muscle wasting more effectively than curcumin. Preservation of muscle mass and reduced hepatic inflammation were associated with down-regulation of the NF-κB canonical pathway and with reduced oxidative stress, respectively. These results point out HPV16-transgenic mice as a useful model for studying the wasting syndrome associated with HPV-induced cancers. Dietary NF-κB inhibitors may be useful resources for treating this syndrome.

Ultrasonography as the Gold Standard for In Vivo Volumetric Determination of Chemically-induced Mammary Tumors.

BACKGROUND/AIM: In this study, we evaluated the dimensions and volume of rat mammary tumors and the association of these variables with tumor invasiveness. MATERIALS AND METHODS: Tumors were measured by caliper and ultrasonography. Volume was determined by water displacement and by application of four formulas using tumor length (L), width (W) and depth (D) or tumor weight. RESULTS: Results confirmed the data obtained in our previous work, where we verified that mammary tumors grow as oblate spheroids. CONCLUSION: The determination of mammary tumor volume by applying the formula V=(4/3)×π×(L/2)×(L/2)×(D/2) is the best way to evaluate tumor volume in vivo. Beyond volume evaluation by water displacement, the determination on the basis of tumor weight is the most accurate way to evaluate tumor volume after animal sacrifice or tumor excision. According to our results, it is not possible to predict if a tumor is invasive or non-invasive by its dimensions, volume or weight. Future work in chemically-induced mammary cancer should use ultrasonography and water displacement or tumor weight to determine tumor volume in vivo and after animal sacrifice or tumor excision, respectively.

Prognostic Factors in an Exercised Model of Chemically-induced Mammary Cancer.

BACKGROUND/AIM: Estrogen receptor α (ERα) and Ki-67 are strong prognostic and predictive markers in woman breast cancer. This study aimed to evaluate the immunoexpression of prognostic factor markers ERα, Ki-67 proliferation index (Ki-67 PI) and the mitotic activity index (MAI) in mammary tumors induced by 1-methyl-1-nitrosourea (MNU) in female Sprague-Dawley rats submitted to lifelong exercise training. MATERIALS AND METHODS: Thirty female rats were injected with MNU and randomly divided into two groups: sedentary and exercised. RESULTS: All neoplasms from both groups were ERα-positive with an H-score ≥20. Statistically significant differences were not found in the ERα H-score, Ki-67 PI and MAI between groups. The absolute value of ERα H-score was higher in the exercised group, while the Ki-67 PI and MAI were higher in the sedentary group. CONCLUSION: Tumors from the exercised group were less proliferative and more differentiated, suggesting that long-term exercise training had positive effects on mammary carcinogenesis.