Prevent Cancer Initiation Research Articles

Molecular pathways: PI3K pathway phosphatases as biomarkers for cancer prognosis and therapy.

Cancer research has seen tremendous changes over the past decade. Fast progress in sequencing technology has afforded us with landmark genetic alterations, which had immediate impact on clinical science and practice by pointing to new kinase targets, such as phosphoinositide 3-kinase (PI3K), the EGF receptor, or BRAF. The PI3K pathway for growth control has emerged as a prime example for both oncogene activation and tumor suppressor loss in cancer. Here, we discuss how therapy using PI3K pathway inhibitors could benefit from information on specific phosphatases, which naturally antagonize the kinase targets. This PI3K pathway is found mutated in most cancer types, including prostate, breast, colon, and brain tumors. The tumor-suppressing phosphatases operate at two levels. Lipid-level phosphatases, such as PTEN and INPP4B, revert PI3K activity to keep the lipid second messengers inactive. At the protein level, PHLPP1/2 protein phosphatases inactivate AKT kinase, thus antagonizing mTOR complex 2 activity. However, in contrast with their kinase counterparts the phosphatases are unlikely drug targets. They would need to be stimulated by therapy and are commonly deleted and mutated in cancer. Yet, because they occupy critical nodes in preventing cancer initiation and progression, the information on their status has tremendous potential in outcome prediction, and in matching the available kinase inhibitor repertoire with the right patients. Clin Cancer Res; 20(12); 3057-63. ©2014 AACR.

6]-gingerol as a cancer chemopreventive agent: a review of its activity on different steps of the metastatic process.

For many years, ginger or ginger root, the rhizome of the plant Zingiber officinale, has been consumed as a delicacy, medicine, or spice. Several studies have been conducted on the medicinal properties of ginger against various disorders, including cancer. Cancer is the second leading cause of death, and chemoprevention is defined as the use of natural or synthetic substances to prevent cancer initiation or progression. Evidence that ginger-derived compounds have inhibitory effects on various cancer cell types is increasingly being reported in the scientific literature. In this review we focused on the cancer chemopreventive effects of [6]-gingerol, the major pungent component of ginger, and its impact on different steps of the metastatic process.

The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer

The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. Although cell signaling pathways triggered by the transcription factor Nrf2 prevent cancer initiation and progression in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth. In this graphical review, we provide an overview of the Keap1-Nrf2 pathway and its dysregulation in cancer cells. We also briefly summarize the consequences of constitutive Nrf2 activation in cancer cells and how this can be exploited in cancer gene therapy.

MiRNA-34 Prevents Cancer Initiation and Progression in a Therapeutically Resistant K-ras and p53-Induced Mouse Model of Lung Adenocarcinoma

Lung cancer is the leading cause of cancer deaths worldwide, and current therapies fail to treat this disease in the vast majority of cases. The RAS and p53 pathways are two of the most frequently altered pathways in lung cancers, with such alterations resulting in loss of responsiveness to current therapies and decreased patient survival. The microRNA-34 (mir-34) gene family members are downstream transcriptional targets of p53, and miR-34 expression is reduced in p53 mutant tumors; thus, we hypothesized that treating mutant Kras;p53 tumors with miR-34 would represent a powerful new therapeutic to suppress lung tumorigenesis. To this end we examined the therapeutically resistant Kras(LSL-G12D)(/+);Trp53(LSL-R172H)(/+) mouse lung cancer model. We characterized tumor progression in these mice following lung-specific transgene activation and found tumors as early as 10 weeks postactivation, and severe lung inflammation by 22 weeks. Tumors harvested from these lungs have elevated levels of oncogenic miRNAs, miR-21 and miR-155; are deficient for p53-regulated miRNAs; and have heightened expression of miR-34 target genes, such as Met and Bcl-2. In the presence of exogenous miR-34, epithelial cells derived from these tumors show reduced proliferation and invasion. In vivo treatment with miR-34a prevented tumor formation and progression in Kras(LSL-G12D)(/+);Trp53(LSL-R172H)(/+) mice. Animals infected with mir-34a-expressing lentivirus at the same time as transgene activation had little to no evidence of tumorigenesis, and lentivirus-induced miR-34a also prevented further progression of preformed tumors. These data support the use of miR-34 as a lung tumor-preventative and tumor-static agent.

Cancer chemoprevention with dietary isothiocyanates mature for clinical translational research

Inverse association between dietary intake of cruciferous vegetables and cancer risk observed in population-based case-control studies is partly attributable to structurally simple but mechanistically complex phytochemicals with an isothiocyanate (-N=C=S) functional group. Cancer protective role for dietary isothiocyanates (ITCs) is substantiated by preclinical studies in rodent models. A common feature of many naturally occurring ITCs relates to their ability to cause growth arrest and cell death selectively in cancer cells. At the same time, evidence continues to accumulate to suggest that even subtle change in chemical structure of the ITCs can have a profound effect on their activity and mechanism of action. Existing mechanistic paradigm stipulates that ITCs may not only prevent cancer initiation by altering carcinogen metabolism but also inhibit post-initiation cancer development by suppressing many processes relevant to tumor progression, including cellular proliferation, neoangiogenesis, epithelial-mesenchymal transition, and self-renewal of cancer stem cells. Moreover, the ITCs are known to suppress diverse oncogenic signaling pathways often hyperactive in human cancers (e.g. nuclear factor-κB, hormone receptors, signal transducer and activator of transcription 3) to elicit cancer chemopreventive response. However, more recent studies highlight potential adverse effect of Notch activation by ITCs on their ability to inhibit migration of cancer cells. Mechanisms underlying ITC-mediated modulation of carcinogen metabolism, growth arrest, and cell death have been reviewed extensively. This article provides a perspective on bench-cage-bedside evidence supporting cancer chemopreventive role for some of the most promising ITCs. Structure-activity relationship and mechanistic complexity in the context of cancer chemoprevention with ITCs is also highlighted.

The Role of Autophagy in Clinical Practice

Resisting cell death is one of the six hallmarks of cancer. Autophagy is a highly adaptable metabolic process that plays an important role in stressful conditions, such as nutrient deprivation and hypoxia. In these conditions, it is becoming evident that autophagy protects cells, by providing an alternative energy source and by eliminating dysfunctional organelles or proteins. In tumourigenesis, autophagy plays a dual role, which may be related to the different stages in cancer development. The autophagy-mediated removal of damaged proteins and organelles may prevent cancer initiation by limiting tissue inflammation. In contrast, autophagy has been shown to allow established tumours to survive in nutrient-deprived or hypoxic conditions during cancer progression. Key regulators of the autophagy pathway are modulated or aberrantly expressed in cancer and modulating autophagy is an attractive concept for cancer therapy. The difficulties, however, lie in the complexity of the crosstalk between apoptosis and autophagy and the lack of robust tissue biomarkers and in vivo assessment of autophagic flux. Currently there are 19 clinical trials in both solid and haematogenous cancers investigating the efficacy and toxicity of adding an autophagy inhibitor to standard treatment. Hydroxychloroquine, a drug routinely used in the treatment of malaria and autoimmune disorders, is the most common autophagy inhibitor under investigation due to its more favourable toxicity profile. This overview summarises the role of autophagy in cancer initiation, progression and resistance to treatment and thereby the therapeutic benefit that may be gained by modulating its effects.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

A Low Carbohydrate, High Protein Diet Slows Tumor Growth and Prevents Cancer Initiation

Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression.

Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis

Carcinogenesis is a multi-step process which could be prevented by phytochemicals. Phytochemicals from dietary plants and other plant sources such as herbs are becoming increasingly important sources of anticancer drugs or compounds for cancer chemoprevention or adjuvant chemotherapy. Phytochemicals can prevent cancer initiation, promotion, and progression by exerting anti-inflammatory and anti-oxidative stress effects which are mediated by integrated Nrf2, NF-kappaB, and AP-1 signaling pathways. In addition, phytochemicals from herbal medicinal plants and/or some dietary plants developed in recent years have been shown to induce apoptosis in cancer cells and inhibition of tumor growth in vivo. In advanced tumors, a series of changes involving critical signaling molecules that would drive tumor cells undergoing epithelial-mesenchymal transition and becoming invasive. In this review, we will discuss the potential molecular targets and signaling pathways that mediate tumor onset and metastasis. In addition, we will shed light on some of the phytochemicals that are capable of targeting these signaling pathways which would make them potentially applicable to cancer chemoprevention, treatment and control of cancer progression.

Targeting the development of resveratrol as a chemopreventive agent

Tumor development consists of several separate, but closely linked, stages: tumor initiation, promotion, and progression. This long and complex process provides opportunities for intervention both in preventing cancer initiation and in treating the neoplasm during its premalignant stages. Resveratrol, a polyphenolic compound found in many plant species, including grapes, peanuts, and various herbs, has recently been investigated intensely for its cancer chemopreventive property. The present work is an overview of the chemopreventive mechanisms of resveratrol in anti-initiation, anti-promotion, and anti-progression. These, together with the low toxicity of resveratrol, suggest promise for novel chemopreventive agents. However, the low bioavailability and rapid clearance of resveratrol from the circulation require the design of new resveratrol-like chemopreventive agents, the structural modifications and the structure–activity relationship of which are also discussed in this review. Drug Dev Res 71:335–350, 2010. © 2010 Wiley-Liss, Inc.

Endotoxin and Cancer

ObjectiveExposure to endotoxin, a component of gram-negative bacterial cell walls, is widespread in many industrial settings and in the ambient environment. Heavy-exposure environments include livestock farms, cotton textile facilities, and saw mills. Concentrations are highly variable in non-occupational indoor and outdoor environments. Endotoxin is a potent inflammagen with recognized health effects, including fever, shaking chills, septic shock, toxic pneumonitis, and respiratory symptoms. Somewhat paradoxically, given the putative role of inflammation in carcinogenesis, various lines of evidence suggest that endotoxin may prevent cancer initiation or limit tumor growth. The hypothesis that components of bacteria may retard cancer progression dates back to William B. Coley’s therapeutic experiments (“bacterial vaccine”) in the 1890s.Data sourcesIn this article, we review epidemiologic, clinical trial, and experimental studies pertinent to the hypothesis that endotoxin prevents cancer. Since the 1970s, epidemiologic studies of cotton textile and other endotoxin-exposed occupational groups have consistently demonstrated reduced lung cancer risks. Experimental animal toxicology research and some limited therapeutic trials in cancer patients offer additional support for an anticarcinogenic potential. The underlying biological mechanisms of anticarcinogenesis are not entirely understood but are thought to involve the recruitment and activation of immune cells and proinflammatory mediators (e.g., tumor necrosis factor α and interleukin-1 and -6).ConclusionsIn view of the current state of knowledge, it would be premature to recommend endotoxin as a cancer-chemopreventive agent. Nonetheless, further epidemiologic and experimental investigations that can clarify further dose–effect and exposure–timing relations could have substantial public health and basic biomedical benefits.

CRM1-Mediated Nuclear Export of Proteins and Drug Resistance in Cancer

Expression levels of intact tumor suppressor proteins and molecular targets of anti-neoplastic agents are critical in defining cancer cell drug sensitivity; however, the intracellular location of a specific protein may be as important. Many tumor suppressor proteins must be present in the cell nucleus to perform their policing activities or for the cell to respond to chemotherapeutic agents. Nuclear proteins needed to prevent cancer initiation or progression or to optimize chemotherapeutic response include the tumor suppressor proteins p53, APC/beta-catenin, and FOXO family genes; negative regulators of cell cycle progression and survival such as p21(CIP1) and p27(KIP1;) and chemotherapeutic targets such as DNA topoisomerases I and IIalpha. Mislocalization of a nuclear protein into the cytoplasm can render it ineffective as a tumor suppressor or as a target for chemotherapy. Blocking nuclear export of any or all of these proteins may restore tumor suppression or apoptosis or, for topoisomerases I and IIalpha, reverse drug resistance to inhibitors of these enzymes. During disease progression or in response to the tumor environment, cancer cells appear to acquire intracellular mechanisms to export anti-cancer nuclear proteins. These mechanisms generally involve modification of nuclear proteins, causing the proteins to reveal leucine-rich nuclear export signal protein sequences. Subsequent export is mediated by CRM1. This review defines the general processes involved in nuclear export mediated by CRM1/RanGTP (exportin/XPO1), examines the functions of individual tumor suppressor nuclear proteins and nuclear targets of chemotherapy, and explores potential mechanisms of cancer cells to induce export of these proteins. Novel drugs that could potentially counteract nuclear export of specific proteins are also discussed.

Cellular mechanisms of tumour suppression by the retinoblastoma gene.

The retinoblastoma (RB) tumour suppressor gene is functionally inactivated in a broad range of paediatric and adult cancers, and a plethora of cellular functions and partners have been identified for the RB protein. Data from human tumours and studies from mouse models indicate that loss of RB function contributes to both cancer initiation and progression. However, we still do not know the identity of the cell types in which RB normally prevents cancer initiation in vivo, and the specific functions of RB that suppress distinct aspects of the tumorigenic process are poorly understood.

Chemoprevention by white currant is mediated by the reduction of nuclear β-catenin and NF-κB levels in Min mice adenomas

Berries are a good natural source of phenolic compounds and many berries or their compounds have been shown to be chemopreventive. White currant is an interesting berry, as it contains low levels of dominant berry phenolics such as ellagic acid, anthocyanins and other flavonoids. To study if white currant is chemopreventive in an experimental model for intestinal tumorigenesis and further study the effects on beta-catenin and NF-kappaB signaling pathways. Multiple intestinal neoplasia (Min) mice were fed an AIN-93G based control diet or a diet containing 10% freeze dried white currant (Ribes x pallidum) for 10 weeks. Cell signaling parameters were analysed from intestinal adenomas and surrounding mucosa by Western blotting and immunohistochemistry. The white currant diet reduced the number of adenomas from 81 (min-max 47-114) to 51 (36-84) in the total small intestine of Min mice (P<0.02). Most of the adenomas develop in the distal part of the small intestine, and in this area white currant reduced the number from 49 to 29.5 (P<0.01) and also the size of the adenomas from 0.88 mm to 0.70 mm (P<0.02). In the colon white currant increased the number of adenomas (0.3+/-0.6 vs. 0.8+/-0.6, mean +/- SD, P<0.05), but did not affect the size. White currant reduced nuclear beta-catenin and NF-kappaB protein levels in the adenomas (P<0.05 and P<0.02, respectively). They were correlated with the size of adenomas (P<0.01). This study shows that white currant is effective in preventing cancer initiation and progression in the Min mouse. Whether the positive effects are due to its special phenolic composition needs to be studied in more detail.

Chemoprevention of Cancer by Isothiocyanates and Anthocyanins: Mechanisms of Action and Structure-Activity Relationship

Carcinogenesis is a multi-step, multi-path and multi-focal process, which involves a series of epigenetic and genetic alterations that begin with genomic instability and end with the development of cancer. This long and complex process presents opportunities for the development of interventions both in preventing cancer initiation and in treating the neoplasm during its premalignant stages. Failure and high systemic toxicity of conventional cancer therapies have accelerated the search for newer agents, which could prevent and/or slow-down cancer growth and have more human acceptability by being less or non-toxic. Now, it is recognized that diets rich in fruits and vegetables are associated with lower risk of cancer. Taking cue from these observations, there is a strong interest in isolating and characterizing the nutritive and non-nutritive components of fruits and vegetables as potential chemopreventive agents. Isothiocyanates and anthocyanins, present in widely consumed fruits and vegetables, are two such agents. In recent years, increasing body of evidence has underscored the cancer preventive efficacy of isothiocyanates and anthocyanins in both in vitro and in vivo animal models. In this review article, we will provide detailed insight into the chemopreventive efficacy of isothiocyanates and anthocyanins based on the evidence generated from various studies performed using cell culture or animal models of epithelial cancers. Moreover, we will discuss the potential clinical relevance of the observed chemopreventive effects of these agents.

Polymorphisms of the DNA Mismatch Repair Gene HMSH2 in Breast Cancer Occurence and Progression

The response of the cell to DNA damage and its ability to maintain genomic stability by DNA repair are crucial in preventing cancer initiation and progression. Therefore, polymorphism of DNA repair genes may affect the process of carcinogenesis. The importance of genetic variability of the components of mismatch repair (MMR) genes is well documented in colorectal cancer, but little is known about its role in breast cancer. hMSH2 is one of the crucial proteins of MMR. We performed a case-control study to test the association between two polymorphisms in the hMSH2 gene: an A --> G transition at 127 position producing an Asn --> Ser substitution at codon 127 (the Asn127Ser polymorphism) and a G --> A transition at 1032 position resulting in a Gly --> Asp change at codon 322 (the Gly322Asp polymorphism) and breast cancer risk and cancer progression. Genotypes were determined in DNA from peripheral blood lymphocytes of 150 breast cancer patients and 150 age-matched women (controls) by restriction fragment length polymorphism and allele-specific PCR. We did not observe any correlation between studied polymorphisms and breast cancer progression evaluated by node-metastasis, tumor size and Bloom-Richardson grading. A strong association between breast cancer occurrence and the Gly/Gly phenotype of the Gly322Asp polymorphism (odds ratio 8.39; 95% confidence interval 1.44-48.8) was found. Therefore, MMR may play a role in the breast carcinogenesis and the Gly322Asp polymorphism of the hMSH2 gene may be considered as a potential marker in breast cancer.

Do soy isoflavones lower cholesterol, inhibit atherosclerosis, and play a role in cancer prevention?

This article is designed to help nursing professionals advise patients about the role of soy in the prevention and treatment of heart disease, breast cancer, and prostate cancer. Soy protein lowers total cholesterol, low-density lipoprotein cholesterol, and triglycerides in humans and inhibits atherosclerosis in animals. In cell culture studies and animal research, the soy isoflavone genistein offers protection from breast cancer and prostate cancer because it prevents cancer initiation, slows promotion, and impedes cancer progression. This article synthesizes the current research concerning soy phytoestrogens and the prevention and treatment of heart disease, breast cancer, and prostate cancer. Nursing professionals may use this information when counseling patients.

Effect of Canthaxanthin on Chemically Induced Mammary Carcinogenesis

Canthaxanthin, a carotenoid with no vitamin A activity, was evaluated for its efficacy in the prevention of chemically induced mammary cancers. Canthaxanthin was administered in the diet at two dose levels (3,390 or 1,130 mg/kg diet). In the dimethylbenzanthracene-induced mammary cancer model, diet supplementation with canthaxanthin for 3 weeks prior to the carcinogen resulted in a 65% reduction in the number of mammary cancers. The feeding of canthaxanthin after the administration of methylnitrosourea had no significant effect on mammary carcinogenesis. These data demonstrate that canthaxanthin, at least in these models of mammary cancer, is active in preventing cancer initiation and not promotion. Analysis of tissues by high-pressure liquid chromatography revealed that canthaxanthin levels in the liver are very high when compared to those in the mammary gland. The observation that canthaxanthin is highly effective in preventing cancer initiation without toxicity suggests that carotenoids not possessing vitamin A activity should be further evaluated as chemopreventive agents.