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Similar to seemingly maladaptive genes in general, the persistence of inherited cancer-causing mutant alleles in populations remains a challenging question for evolutionary biologists. In addition to traditional explanations such as senescence or antagonistic pleiotropy, here we put forward a new hypothesis to explain the retention of oncogenic mutations. We propose that although natural defenses evolve to prevent neoplasm formation and progression thus increasing organismal fitness, they also conceal the effects of cancer-causing mutant alleles on fitness and concomitantly protect inherited ones from purging by purifying selection. We also argue for the importance of the ecological contexts experienced by individuals and/or species. These contexts determine the locally predominant fitness-reducing risks, and hence can aid the prediction of how natural selection will influence cancer outcomes. [ABSTRACT FROM AUTHOR]

A bstract Tumor cells of the muscle-related cancer alveolar rhabdomyosarcoma (aRMS) have dysregulated terminal myogenic differentiation that is characterized by continuous proliferation, decreased capacity to express markers of terminal differentiation, and inability of tumor cells to fuse to one another in the manner seen for normal myoblasts. Whether aRMS tumor cells can fuse with normal myogenic progenitors such as skeletal muscle stem cells (satellite cells) or myoblasts is unknown, as is the biological effect of fusion events if the phenomenon occurs. To study this possibility, we isolated primary satellite cells harboring a lacZ Cre-LoxP reporter gene for coculture with murine aRMS primary tumor cells expressing Cre. Results of in vitro and in vivo experiments demonstrated tumor cell-muscle cell progenitor fusion events as well as accelerated rates of tumor establishment and progression when satellite cells and derived muscle progenitors were coinjected with tumor cells in an orthotopic allograft model. Interleukin 4 receptor (IL-4R) blocking antibody treatment reversed fusion events in vitro and blocked tumor initiation and progression in vivo. Taken together, this study supports a potential role of tumor cell-host cell fusion and the strong therapeutic potential of IL-4R blockade to prevent the establishment of RMS tumors at new anatomical sites. S tem C ells 2013;31:2304-2312 [ABSTRACT FROM AUTHOR]

The article discusses the results of a study examining the effectiveness of food ingredients for therapeutic applications. The study focuses on the role of mulberry 1-deoxynojirimycin in α-glucosidase inhibition and in the digestion of carbohydrates. It evaluates the efficiency of rice bran tocotrienol in inhibiting tumor growth and its potential as anticancer agents. The use of antioxidative and antiglycative compounds to suppress membrane lipid peroxidation/glycation was also studied.

Purpose: Colorectal cancer (CRC) is associated with high recurrence and mortality. Because deregulation of microRNAs is associated with CRC development and recurrence, the expression levels of microRNAs can be a simple and reliable biomarker to detect postoperative early relapse, thereby helping physicians to treat high-risk patients more efficiently. Experimental design: We used microRNA arrays and observed that microRNA-93 had substantially different expression levels in early (recurrence within 12 months after surgery) and non-early relapse CRC patients. The replication study, which included 35 early relapse and 42 non-early relapse subjects, further confirmed overexpression of microRNA-93 in non-early relapse samples. The in vitro and in vivo effects of microRNA-93 were investigated by examining cell proliferation, migration and invasion, as well as cell cycles, target-gene expression and xenograft in null mice. Results: Cellular studies showed that the overexpression of microRNA-93 inhibited colon cancer cell proliferation and migration but not invasion. The cell cycle studies also revealed that microRNA-93 caused an accumulation of the G2 population. However, microRNA-93 could not induce cell apoptosis or necrosis. Functional studies showed that microRNA-93 could suppress CCNB1 protein expression leading to cell cycle arrest in the G2 phase. Moreover, microRNA-93 repressed expression of ERBB2, p21 and VEGF, all of which are involved in cell proliferation. MicroRNA-93 also suppressed tumor growth in null mice. Conclusions: This study showed that microRNA-93 can inhibit tumorigenesis and reduce the recurrence of CRC; these findings may have potential clinical applications for predicting the recurrence of CRC. [ABSTRACT FROM AUTHOR]

Previous studies have shown that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27kip1 and E-cadherin and an upregulation of β-catenin signaling [Bi,X. et al. (2008) Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation. Carcinogenesis, 29, 1435–1440]. However, the regulation of E-cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using a decorin knockout mouse model (Dcn−/− mice) and manipulated expression of decorin in human colorectal cancer cells, we found that E-cadherin, a protein that regulates cell–cell adhesion, epithelial–mesenchymal transition and metastasis, was almost completely lost in Dcn−/− mouse intestine, and loss of decorin and E-cadherin accelerated colon cancer cell growth and invasion in Dcn−/− mice. However, increasing decorin expression in colorectal cancer cells attenuated cancer cell malignancy, including inhibition of cancer cell proliferation, promotion of apoptosis and importantly, attenuation of cancer cell migration. All these changes were linked to the regulation of E-cadherin by decorin. Moreover, overexpression of decorin upregulated E-cadherin through increasing of E-cadherin protein stability as E-cadherin messenger RNA and promoter activity were not affected. Co-immunoprecipitation assay showed a physical binding between decorin and E-cadherin proteins. Taken together, our results provide direct evidence that decorin-mediated inhibition of colorectal cancer growth and migration are through the interaction with and stabilization of E-cadherin. [ABSTRACT FROM PUBLISHER]

Naturally occurring allyl isothiocyanate (AITC) was recently shown to be selectively delivered to bladder cancer tissue via urinary excretion and to inhibit bladder cancer growth and muscle invasion in an animal model. AITC is excreted in urine mainly as N-acetyl-S-(N-allylthiocarbamoyl)cysteine, more commonly known as the N-acetylcysteine conjugate (NAC-AITC). We show here that treatment of human bladder cancer UM-UC-3 cells or rat bladder cancer AY-27 cells with NAC-AITC at 15 μM results in significant inhibition of cell growth and proliferation, together with cell cycle arrest and apoptosis. We also show that NAC-AITC administered orally at 10 μmol/kg body wt inhibits cancer growth by 40% and muscle invasion by 49% in an orthotopic rat bladder cancer model. Furthermore, the anticancer activity of NAC-AITC is associated with the modulation of several important molecular targets, including downregulation of both α-tubulin and β-tubulin, activation of caspase-3 and downregulation of vascular endothelial growth factor. These results are similar to those shown previously for AITC and are consistent with the understanding that NAC-AITC is a carrier of AITC. Furthermore, comparison of the pharmacokinetic and physical properties of NAC-AITC with those of AITC suggests that NAC-AITC is superior to AITC for potential use for prevention and therapy of bladder cancer. [ABSTRACT FROM PUBLISHER]

We investigated the effects of caloric restriction (CR) on growth of tumors and metastases in the 4T1 mammary tumor model and found that CR, compared with normal diet, reduced the growth of mammary tumors and metastases and the total number of metastases that originated both spontaneously from the primary tumor and also experimentally from i.v. injection of the tumor cells. CR also decreased proliferation and angiogenesis and increased apoptosis in tumors. CR reduced levels of insulin, leptin, insulin-like growth factor 1, insulin-like growth factor binding protein 3 and increased adiponectin in tumors. We also demonstrated that tumors from CR mice possessed lower levels of transforming growth factor-β, lower intratumor deposition of collagen IV and reduced invasiveness due to a decrease in tumor secretion of active matrix metalloproteinase 9. Our results suggest that CR-induced metabolic and signaling changes affect the stroma and the tumor cells resulting in a microenvironment that prevents proliferation of breast tumors and their metastases. [ABSTRACT FROM AUTHOR]

M3 subtype muscarinic receptors (CHRM3) are over-expressed in colon cancer. In this study, we used Apcmin/+ mice to identify the role of Chrm3 expression in a genetic model of intestinal neoplasia, explored the role of Chrm3 in intestinal mucosal development and determined the translational potential of inhibiting muscarinic receptor activation. We generated Chrm3-deficient Apcmin/+ mice and compared intestinal morphology and tumor number in 12-week-old Apcmin/+Chrm3−/− and Apcmin/+Chrm3+/+ control mice. Compared with Apcmin/+Chrm3+/+ mice, Apcmin/+Chrm3−/− mice showed a 70 and 81% reduction in tumor number and volume, respectively (P < 0.01). In adenomas, β-catenin nuclear staining was reduced in Apcmin/+Chrm3−/− compared with Apcmin/+Chrm3+/+ mice (P < 0.02). Whereas Apc gene mutation increased the number of crypt and Paneth cells and decreased villus goblet cells, these changes were absent in Apcmin/+Chrm3−/− mice. To determine whether pharmacological inhibition of muscarinic receptor activation attenuates intestinal neoplasia, we treated 6-week-old Apcmin/+ mice with scopolamine butylbromide, a non-subtype-selective muscarinic receptor antagonist. After 8 weeks of continuous treatment, scopolamine butylbromide-treated mice showed a 22% reduction in tumor number (P = 0.027) and a 36% reduction in tumor volume (P = 0.004) as compared with control mice. Compared with Chrm3 gene ablation, the muscarinic antagonist was less efficacious, most probably due to shorter duration of treatment and incomplete blockade of muscarinic receptors. Overall, these findings indicate that interplay of Chrm3 and β-catenin signaling is important for intestinal mucosal differentiation and neoplasia and provide a proof-of-concept that pharmacological inhibition of muscarinic receptor activation can attenuate intestinal neoplasia in vivo. [ABSTRACT FROM AUTHOR]

The article presents a study on the synthesis and biological evaluation of a dimethyl derivative of Aplog-1, an anti-proliferative analog of the tumor promoter aplysiatoxin. It notes that the Aplog-1 (3) derivative was effective in inhibiting cancer cell growth and binding to particular protein kinases. It also notes that the derivative shows potential for anti-cancer drugs.

The article focuses on a study which evaluated the effect of portal branch ligation (PBL) on angiogenesis, growth factor expression and tumour growth in a mouse model of hepatic colorectal metastases. Angiogenesis, microcirculatlon, growth factor expression, cell proliferation and tumour growth were assessed in the mice that underwent PBL of the left liver lobe or sham. Study authors concluded that PBL initially reduced vascular perfusion and tumour growth.

The article discusses combination chemotherapy regimens for the treatment of metastatic breast cancer. Combination drug therapy regimens include both cytotoxic and noncytotoxic agents including ixabepilone with capecitabine and lapatinib with capecitabine. Endocrine agents are the first-line treatment for patients with metastatic breast cancer involving tumors which express estrogen or progesterone receptors. The safety and efficacy of combination chemotherapy requires further study.

The article discusses the therapeutic and pharmacological uses of cat's claw, which is a thick woody vine indigenous to the Amazon rain forest and other tropical areas of South and Central America. Several species exist and it is thought that the vine may have the ability to strengthen the immune system, inhibit inflammation and tumor growth as well as suppress viral replication.

The article presents a prospective study aimed at developing a predictive model using preoperative information to aid selection for nipple-sparing mastectomy. To carry out the study, 200 consecutive skin-sparing mastectomy specimens without overt nipple involvement were evaluated. Findings indicate that three-quarters of women undergoing mastectomy did not have occult nipple involvement. As a response, a clinical tool including tumour size and distance from the nipple was developed.

The article presents a study on the anticancer mechanisms of indole-3-carbinol (I3C) in terms of suppressing tumor-induced angiogenesis and tube formation of endothelial cells. The study include planting of saline tumor cells, control diet feeding and negative and positive control group air sac assay were performed into mice. It also presents the effects of I3C on tube formation, the molecular difference of tube formation and growth phase, and the apoptotic changes in endothelial cells.

This article presents research into the role of Interleukin-8 (IL-8), a proarigiogenic cytokine, in many human cancers. Using human samples and orthotopic mouse models, the authors investigated the clinical and biologic significance of IL-8 in ovarian carcinoma. In over 100 specimens, 42% had high levels of IL-8.

Using modelling, we have developed a treatment strategy for gliomas exhibiting low dose hyper-radiosensitivity (HRS) that employs both a reduced dose-rate and pulsed treatment dose delivery. The model exploits the low dose hypersensitivity observed in some glioma cell lines at low radiation doses. We show, based on in vitro data, that a pulsed delivery of external beam radiation therapy could yield significant increases in local control. We therefore propose a pulsed delivery scheme for the treatment of gliomas in which the daily treatment fraction is delivered using 0.20 Gy pulses, separated by three minutes for a time-averaged dose-rate of 0.0667 Gy/min. The dose per pulse of 0.2 Gy is near or below the transition dose observed in vitro for four of the five glioma cell lines we have studied. Using five established glioma cell lines our modelling demonstrates that our pulsed delivery scheme yields a substantial increase in tumour control probability (TCP). [ABSTRACT FROM AUTHOR]

The article presents a study on the use of butyrate in suppressing a cancer cell in Japan. Butyrate is a derivative of the butyric acid which may be from a form of an ester or a salt. The research was conducted to help make a concrete idea conforming to the previous results which the study recorded a significant reduction of tumor. Similar to the previous studies, the fatty acid was able to inhibit the metastasis of the cancer cells.

Heterocyclic amines (HCAs) have been shown to induce tumors in several organs of rodents, but except for MeIQ and PhIP, other HCAs such as MeIQx and IQ consistently failed to induce colon tumors in mice, whereas MeIQ, IQ, and PhIP exerted colon tumorigenicity in rats. Recently, we found that dietary MeIQx induces genotoxicity in the colon as well as the liver of two different types of reporter gene transgenic mice at subcarcinogenic doses such as 300 ppm. However, in the present study, dietary MeIQx did not significantly induce any tumors in C57BL/6J mice or gpt delta mice even when fed at 300 ppm for 78 weeks, suggesting that the treatment of MeIQx alone was not sufficient to promote colon tumors. In order to clarify a possibility whether such HCAs can induce colon tumors, C57BL/6J mice were fed MeIQx, IQ, or PhIP at a dose of 300 ppm for 12 weeks and, thereafter, twice received 1-week treatment with dextran sulfate sodium (DSS), 2 weeks apart. After 20 weeks, colon tumors including adenocarcinomas were found at incidences of 22%, 24%, and 45% in the groups receiving MeIQx, IQ, and PhIP, respectively, which were significantly (p < 0.05 or 0.01) different from the DSS alone value (0%). Thus our results clearly indicate that, in addition to PhIP, MeIQx and IQ can induce colon tumors in mice under an experimental condition promoting colon tumors. [ABSTRACT FROM AUTHOR]

Examines the efficacy of interleukin 12 electro-gene therapy in the reduction of tumor growth. Determination of antiangiogenic effects and an immune response; Induction of long-term antitumor memory; Application of the therapy for electrode-accessible malignancies.

Increased expression of the molecule CD200 in mice receiving renal allografts is associated with immunosuppression leading to increased graft survival, and altered cytokine production in lymphocytes harvested from the transplanted animals. Preferential production of IL-4, IL-10 and TGFβ occurs on donor-specific restimulation in vitro, with decreased production of IL-2, IFNγ and TNFα. These effects are enhanced by simultaneous infusion of CD200 immunoadhesin (CD200Fc) and donor CD200 receptor (CD200r) bearing macrophages to transplanted mice. C57BL/6 mice do not normally resist growth of EL4 or C1498 leukaemia tumour cells. Following transplantation of cyclophosphamide-treated C57BL/6 with T-depleted C3H bone marrow cells, or for the EL4 tumour, immunization of C57BL/6 mice with tumour cells transfected with a vector encoding the co-stimulatory molecule CD80 (EL4-CD80), mice resist growth of tumour challenge. Immunization of C57BL/6 mice with EL4 cells overexpressing CD86 (EL4-CD86) is ineffective. Protection from tumour growth in either model is suppressed by infusion of CD200Fc, an effect enhanced by co-infusion of CD200r+ macrophages. CD200Fc acts on both CD4+ and CD8+ cells to produce this suppression. These data are consistent with the hypothesis that immunosuppression following CD200–CD200r interaction can regulate a functionally important tumour growth inhibition response in mice. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase 4 (Cdk4) represents a prime target for the treatment of cancer because most human cancers are characterized by overexpression of its activating partner cyclin D1, loss of the natural Cdk4-specific inhibitor p16, or mutation(s) in Cdk4's catalytic subunit. All of these can cause deregulated cell growth, resulting in tumor formation. We sought to identify a small molecule that could inhibit the kinase activity of Cdk4 in vitro and to then ascertain the effects of that inhibitor on cell growth and tumor volume in vivo.Methods: A triaminopyrimidine derivative, CINK4 (a chemical inhibitor of Cdk4), was identified by screening for compounds that could inhibit Cdk4 enzyme activity in vitro. Kinase assays were performed on diverse human Cdks and on other kinases that were expressed in and purified from insect cells to determine the specificity of CINK4. Cell cycle effects of CINK4 on tumor and normal cells were studied by flow cytometry, and changes in phosphorylation of the retinoblastoma protein (pRb), a substrate of Cdk4, were determined by western blotting. The effect of the inhibitor on tumor growth in vivo was studied by use of tumors established through xenografts of HCT116 colon carcinoma cells in mice. Statistical tests were two-sided.Results: CINK4 specifically inhibited Cdk4/cyclin D1 in vitro. It caused growth arrest in tumor cells and in normal cells and prevented pRb phosphorylation. CINK4 treatment resulted in statistically significantly (P: =.031) smaller mean tumor volumes in a mouse xenograft model.Conclusions: Like p16, the natural inhibitor of Cdk4, CINK4 inhibits Cdk4 activity in vitro and slows tumor growth in vivo. The specificity of CINK4 for Cdk4 raises the possibility that this small molecule or one with a similar structure could have therapeutic value. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) can either promote angiogenesis (i.e., the formation of new blood vessels) in tumors by secreting tumor necrosis factor-alpha (TNF-alpha) or inhibit angiogenesis by producing granulocyte-macrophage colony-stimulating factor (GM-CSF), which in turn stimulates production of the antiangiogenic protein plasminogen activator inhibitor type 2 (PAI-2). We tested, alone or in combination, the anti-prostate cancer activity of agents that perturb macrophage function.Methods: By use of enzyme-linked immunosorbent assays, we measured the effects of Linomide (roquinimex), thalidomide, pentoxifylline, and genistein on TNF-alpha and GM-CSF production in vitro by virally transformed RAW 264.7 mouse macrophages and on PAI-2 production in vitro by human macrophages. The antitumor effects of these agents were tested in vivo on transplanted Dunning R-3327 MAT-Lu rat prostate cancers; TAM numbers and blood vessel densities in these cancers were determined by use of immunocytochemistry.Results: Linomide selectively inhibited mouse macrophage secretion of TNF-alpha but not of GM-CSF; however, thalidomide, pentoxifylline, and genistein inhibited the production of both cytokines. Linomide, but not thalidomide or pentoxifylline, increased production of PAI-2 by human macrophages. When administered to rats bearing MAT-Lu tumors, each of the tested agents reduced TAM numbers (Linomide, by 46%; thalidomide, by 94%; pentoxifylline, by 71%; and genistein, by 96%). However, all of the agents reduced tumor blood vessel density and tumor growth, with Linomide being the most effective (44% reduction in blood vessel density and 69% inhibition of tumor growth). None of the other agents potentiated Linomide's antitumor effect.Conclusions: Linomide is unique among the antiangiogenic agents tested, in that it inhibits the stimulatory effects of TAMs on tumor angiogenesis without eliminating their antiangiogenic effects, and may thus prove to be more effective against prostate cancer. [ABSTRACT FROM AUTHOR]

Determines the extent to which anti-interleukin and anti-transferrin receptor antibodies when used individually or combined could limit myeloma cell growth. Dose-dependent growth inhibition of varying degrees on myeloma cells; Loss of colony-forming capability by factor-dependent myeloma cells exposed to receptor antibodies.

The article presents a study that investigates the effectiveness of anthracyclines in preventing tumor growth and hypxia-inducible factor 1 (HIF-1). The study reveals that anthracyclines can help kill cancer cells through the intervention of DNA replication as well as regulate oxygen metabolism. The study notes that a special inhibitor is present during the process which effectively suppress angiogenesis and stimulates endothelial cell growth.

The author discusses the role of the transforming growth factor beta (TGF-β) in cancer. He states that the TGF-β functions as a potent tumor suppressor during the early stages of carcinoma development. In the later stage, it can promote tumor progression by facilitating cell invasion and metastasis. He believes that the mechanistic role of TGF-β in cancer has implications in the design and use of different TGF-β pathway inhibitors.

The treatment planning approach used within the heavy ion tumour therapy project at GSI Darmstadt includes a biological optimisation, which is based on a biophysical model, the Local Effect Model (LEM). Here we show that the predictions of the LEM are in good agreement with clinical data obtained at the HIMAC in Chiba for the treatment of non-small-cell lung cancer, and the steep dose response for carbon ions is reproduced correctly. This steeper increase corresponds to an increasing RBE with increasing dose, which apparently is in contradiction to the systematics observed in general for in vitro measurements. A possible explanation of this discrepancy is based on the interindividual variation of photon sensitivity. [ABSTRACT FROM PUBLISHER]

BACKGROUND Epigallocatechin-3-gallate (EGCG), the major component of green tea, is a pleiotropic substance, which may inhibit tumor growth via multiple intracellular signaling pathways. Herein, we studied whether EGCG may also be effective in the treatment of endometriosis. METHODS We investigated the effect of EGCG on activation by estradiol (E2), proliferation and vascular endothelial growth factor (VEGF) expression of isolated hamster endometrial stromal cells and glandular cells in vitro using the water-soluble tetrazolium (WST)-1 colorimetric assay and western blot analysis. In the dorsal skinfold chamber model of Syrian golden hamsters, which were treated for 14 days with EGCG or vehicle, we further analyzed angiogenesis, blood perfusion and tissue integrity of both endometriotic lesions and ovarian follicles by intravital fluorescence microscopy and histology. RESULTS We found that EGCG suppresses E2-stimulated activation, proliferation and VEGF expression of endometrial cells in vitro (all P P in vivo without affecting blood vessel development in ovarian follicles. Histology confirmed that EGCG-treatment induces regression of the endometriotic lesions. CONCLUSIONS Our data indicate that EGCG might be a promising therapeutic agent in the treatment of endometriosis, preventing the establishment of new endometriotic lesions. [ABSTRACT FROM AUTHOR]

Reports that tumors could be kept dormant by blocking angiogenesis. Process by which tumors establish the vascular tentacles that nourish the tumors and provide their deadly access to other sites in the body; Keynote speech delivered by Judah Folkman on the subject; Pharmaceutical companies making angiogenesis inhibitors.