A retrospective (N = 140) and a prospective (N = 102) observational Israeli study by Bar-Sela and colleagues about cannabis potentially adversely impacting the response to immunotherapy have together been cited 202 times, including by clinical practice guidelines. There have also been concerns on PubPeer outlining irregularities and unverifiable information in their statistics and numerous errors in calculating percentages. This reanalysis attempted to verify the data analysis while including non-parametric statistics. The corrected prospective report contained 22 p-values, but only one (4.5%) could be verified despite the authors being transparent about the N and statistics employed. Cannabis users were significantly (p < 0.0025) younger than non-users, but this was not reported in the retrospective report. There were also errors in percentage calculations (e.g., 13/34 reported as 22.0% instead of 38.2%). Overall, these observational investigations, and especially the prospective, appear to contain gross inaccuracies which could impact the statistical decisions (i.e., significant findings reported as non-significant or vice-versa). Although it is mechanistically plausible that cannabis could have immunosuppressive effects which inhibit the response to immunotherapy, these two reports should be viewed cautiously. Larger prospective studies of this purported drug interaction that account for potential confounds (e.g., greater nicotine smoking among cannabis users) may be warranted.
Primary tumors can inhibit the growth of secondary lesions, particularly metastases, in a phenomenon termed "concomitant resistance". Several mechanisms have been proposed for this effect, each supported by experimental data. In this paper, we hypothesize that concomitant resistance is a form of hormesis, a biphasic dose response in which a stimulus has a positive and/or stimulatory effect at low dosages and a negative, inhibitory, and/or toxic effect at higher dosages. When this paradigm applies to tumorigenesis, it is referred to as "cancer hormesis". Thus, low numbers of benign neoplastic cells or less tumorigenic malignant cells may result in resistance to the development of malignant neoplasms, including metastases. A host containing a number of (less tumorigenic) neoplastic cells may exhibit greater protection against more tumorigenic malignant neoplasms than a host who lacks neoplastic cells, or who has too few neoplastic cells to stimulate a protective response. As a theoretical endeavor, this paper also proposes that cancer hormesis can be leveraged for therapeutic purposes, by the implantation of safely controlled, benign artificial tumors in high-risk patients. These tumors would prevent the development of endogenous malignant neoplasms by creating an inhibitory environment for such growth. Strategies for testing the hypothesis are proposed.
Teams and the promotion of teamwork for both faculty and for students can be key components of integrated curriculum and 'flipped classroom' active learning approaches for medical education. The benefits of teams and teamwork are presented to faculty and students, sometimes via indoctrination, but the costs of the team approach, balanced against the purported benefits, are typically not discussed. This unbalanced presentation creates the need for a statement of a contrarian view. I posit that among the problems of teams and teamwork in education are diminishment of individual initiative and individual responsibility, lowering standards to the least common denominator, creating excess obligations with respect toward weaker team members, negative effects on academic freedom, inconsistency with respect to how faculty and students are evaluated, and giving students a somewhat false view of their accountability as a medical professional. Possible ideological considerations and attitudes toward individualism with respect to teams need to be understood as well.
Medical school curriculums have increasingly shifted to an integrated curriculum and have been replacing lecture with 'flipped classroom' approaches. Analyses of the benefits of the integrated curriculum and flipped classroom model typically report enhanced student performance. However, the question is whether institutional self-evaluation of curricular success is biased to demonstrate success that may not objectively exist and/or whether such biased data are presented during Liaison Committee on Medical Education (LCME) site visits. An objective determination of curricular effectiveness requires an absence of bias and of efforts to put an institutional 'thumb on the scale' to obtain desired results. In addition, bias may exist in the rationale for implementing these curricular changes in the first place; these can include, for example, with respect to career advancement as well as ideological motivation. Thus, in this paper I examine potential problems with institutional bias with evaluation of curriculum and how to overcome these.
Autosomal dominant diseases typically have an age-related onset. Here, I focus on genetic prion disease (gPrD), caused by various mutations in the PRNP gene. While gPrD typically occurs at or after middle age, there can be considerable variability in the specific age of onset. This variability can occur among patients with the same PRNP mutation; in some cases, these differences occur not only between families but even within the same family. It is not known why gPrD onset is typically delayed for decades when the causative mutation is present from birth. Mouse models of gPrD manifest disease; however, unlike human gPrD, which typically takes decades to manifest, mouse models exhibit disease within months. Therefore, the time to onset of prion disease is proportional to species lifespan; however, it is not known why this is the case. I hypothesize that the initiation of gPrD is strongly influenced by the process of aging; therefore, disease onset is related to proportional functional age (e.g., mice vs. humans). I propose approaches to test this hypothesis and discuss its significance with respect to delaying prion disease through suppression of aging.
Prion Diseases , Prions , Middle Aged , Humans , Animals , Mice , Prions/genetics , Prion Proteins/genetics , Prion Diseases/genetics , Mutation
Deregulated Wnt signaling is responsible for most cases of colorectal cancer (CRC). Dietary fiber is protective against CRC and this activity is likely mediated by butyrate, a breakdown product of dietary fiber that hyperactivates Wnt signaling, repressing CRC proliferation and inducing apoptosis. Receptor-mediated Wnt signaling and oncogenic Wnt signaling, which is typically initiated by mutation in more downstream elements of the pathway, activate non-overlapping patterns of gene expression. Receptor-mediated signaling is associated with a poor prognosis for CRC while oncogenic signaling is associated with a relatively good prognosis. We have compared the expression of genes differentially expressed in receptor-mediated vs. oncogenic Wnt signaling to microarray data generated in our laboratory. Most importantly we evaluated these gene expression patterns comparing the early stage colon microadenoma line LT97 with the metastatic CRC cell line SW620. LT97 cells exhibit a gene expression pattern more strongly associated with that observed with oncogenic Wnt signaling, while SW620 cells exhibit a gene expression pattern moderately associated with that observed with receptor-mediated Wnt signaling. Given that SW620 cells are more advanced and malignant compared to LT97 cells, these findings are generally consistent with the better prognosis observed with tumors exhibiting a more oncogenic Wnt gene expression pattern. Importantly, LT97 cells are more sensitive to the effects of butyrate on proliferation and apoptosis that are CRC cells. We further examine these gene expression patterns in butyrate-resistant vs. butyrate-sensitive CRC cells. Based upon all of these observations, we hypothesize that colonic neoplastic cells exhibiting a more oncogenic as compared to receptor-mediated Wnt signaling gene expression pattern would be more sensitive to the effects of butyrate, and, hence, fiber, than are those cells exhibiting a more receptor-mediated Wnt signaling pattern of expression. Diet-derived butyrate may affect the differential patient outcomes resulting from the two types of Wnt signaling. We further posit that development of butyrate resistance and concomitant changes in Wnt signaling patterns, including associations with CBP and p300, disrupts the association between the two major types of Wnt signaling (receptor-mediated and oncogenic) and neoplastic progression/prognosis. Ideas about testing the hypothesis and therapeutic implications are briefly considered.
Tumorigenesis typically requires the accumulation of several driver gene mutations; therefore, there is a mutation threshold for the completion of the neoplastic process. Obesity increases the risk of cancer, and we have proposed that one mechanism whereby obesity raises the risk of microsatellite stable (MSS) colon cancer is by decreasing the mutation threshold. Therefore, obese MSS colon cancer patients should exhibit fewer driver gene mutations compared to normal body-mass index (BMI) patients. Our hypothesis is supported by results from analyses of The Cancer Genome Atlas (TCGA) data, which revealed that cancer genomes of obese MSS colon patients exhibit both fewer somatic mutations and fewer driver gene mutations. These findings could be explained by the high levels of obesity-associated cytokines and factors, the signaling pathways of which substitute for the additional driver gene mutations detected in normal-weight MSS colon cancer patients. Therefore, obesity-induced aberrant cell signaling might cooperate with initiating driver gene mutations to promote neoplastic development. Consistent with this possibility, we observed a lower number of KRAS mutations in high-BMI MSS colon cancer patients. This paper extends our hypothesis to address the interactions between obesity, immune surveillance in neoplastic development, and colorectal cancer (CRC) risk. A better understanding of these interactions will inform future preventive and therapeutic approaches against MSS CRC. We propose that the individual variations in the major histocompatibility class 1 (MHC-1) genotype interact with obesity to shape the tumor mutational landscape. Thus, the efficiency of the immune surveillance mechanisms to select against specific mutations may depend on both the MHC-1 genotype variant and the BMI of an individual. A high BMI is expected to reduce the number of driver gene mutations required to evade the MHC-1 surveillance mechanism and support an accelerated cancer progression.
The multiple-hit hypothesis of cancer, including colorectal cancer (CRC), states that neoplastic development requires a sequence of mutations and epigenetic changes in driver genes. We have previously proposed that obesity increases CRC risk by supporting neoplastic development through adipokine-induced signaling, and this proliferative signaling substitutes for specific driver gene mutations. In support of this hypothesis, analyses of The Cancer Genome Atlas (TCGA) mutation data have revealed that obese patients with microsatellite stable CRC exhibit fewer driver gene mutations than CRC patients with normal body mass index. The lower number of driver gene mutations required for cancer development may shorten the neoplastic process and lead to an early onset of CRC. Therefore, obesity could be one factor explaining the rise of CRC incidence among younger individuals (< 50 years of age); furthermore, early onset CRC has been associated with the increasing incidence of metabolic syndrome and obesity in this age group. However, CRC incidence among older individuals (> 50 years of age) is stable or declining, despite the high rates of metabolic syndrome and obesity in this age group. In search for explanations of this phenomenon, we discuss several factors that may contribute to the divergent CRC incidence trends in populations under, and above, the age of 50, despite the rising levels of metabolic syndrome and obesity across all ages. First, older individuals with metabolic dysregulation are more frequently on maintenance medications, such as aspirin, ß-blockers, lipid-lowering drugs, ACE inhibitors, metformin, etc., compared to younger individuals. Such treatments may suppress specific adipokine-induced proliferative signaling pathways, and therefore counteract and slow down neoplastic development in medicated overweight/obese individuals. Second, in the past decades, the incidence of infectious diseases accompanied by febrile episodes has been decreasing and the use of antipyretics increasing. Compared to normal cells, neoplastic cells are more sensitive to high body temperature; therefore, the decreased number of febrile episodes in childhood and adolescence may contribute to increased cancer incidence before the age of 50. Third, obesity at younger age may expand the stem cell compartment. An increased number of intestinal stem cells and stem cell divisions translates into a higher probability of sporadic mutations in the stem cells, and therefore, a greater chance of neoplasia. In conclusion, we hypothesize that early onset CRC has multifactorial causation and the proposed associations could be examined through analyses of existing data.
The preventive activity of dietary fiber against colorectal cancer (CRC) may be in part mediated by the fermentation product of fiber, butyrate, a histone deacetylase inhibitor (HDACi) that induces CRC cell growth arrest and apoptosis. This action of butyrate, and other HDACis, is in part due to the hyperactivation of the deregulated Wnt activity found in the relevant CRC cell lines. The histone acetylases CBP and p300 interact with beta-catenin; and the relative levels of CBP-Wnt vs. p300-Wnt activity influences CRC cell physiology. It has previously been observed that there are cell type-specific differences in how cotreatment with butyrate and ICG-001, an agent that blocks CBP-Wnt activity allowing for p300-Wnt activity, affects CRC cell physiology. These differences may have clinical significance in dealing with treatment of CRC patients with ICG-001-like agents. Sam68 is a factor differentially expressed in cancer cells, with higher expression in cancer cell lines that have cancer stem cell (CSC)-like properties. Sam68 expression sensitizes cancer cells to ICG-001 treatment, as ICG-001 enhances nuclear localization of Sam68, where binding between Sam68 and CBP diminishes CBP-beta-catenin binding and thus CBP-Wnt activity. Pygo2 is a chromatin effector involved with Wnt signaling that is differentially acetylated by CBP and p300; thus CBP-mediated acetylation localized Pygo2 to the nucleus where it functions in transcriptional activation, while p300-mediated acetylation localizes Pygo2 to the cytoplasm. This paper proposes the hypothesis that Sam68 and Pygo2 are responsible for cell type-specific response of CRC cell lines cotreated with ICG-001 and butyrate as well as other HDACis. Further, experiments are proposed to evaluate this hypothesis and consider possible expected results that could be obtained from such studies.
Butyrate, a product of dietary fiber, hyperactivates Wnt signaling in colorectal cancer (CRC) cells; this activity of butyrate is causally associated with the induction of apoptosis, and the repression of proliferation, in these cells. However, CRC can develop despite a high fiber diet; hence, butyrate resistance likely occurs during colonic neoplasia. To evaluate the mechanisms of butyrate resistance, HCT-116 CRC cells were previously made resistant to butyrate (HCT-R cell line); I observed that butyrate resistance in HCT-R cells is accompanied by repressed Wnt hyperactivation. CBP and p300 competitively bind to the Wnt signaling factor beta-catenin; CBP-Wnt activity is associated with proliferation, while p300-Wnt activity is associated with differentiation and apoptosis. While butyrate sensitive HCT-116 cells express p300, butyrate resistant HCT-R cells do not. Further, HCT-116 p300 knockout cells exhibit butyrate resistance, and restoration of p300 expression in these cells enhances butyrate sensitivity. Thus, p300 activity is a mediator of butyrate sensitivity in HCT-116-derived cell lines. In the present study, YH249, a pharmacological inhibitor of the p300-beta-catenin association, was utilized to more specifically evaluate the role of p300-Wnt signaling in butyrate responsiveness. Unexpectedly, YH249 potentiates butyrate-induced effects on apoptosis and cell proliferation in HCT-116 cells; in addition, potential off-target, p300-independent, effects of YH249 on butyrate-induced Wnt hyperactivation were observed. SW620 metastatic CRC cells express p300, but do not exhibit association of p300 with beta-catenin. Thus, I hypothesized that SW620 cells can be made butyrate resistant without loss of p300 expression, while butyrate resistance would still be associated with repressed Wnt hyperactivation; this hypothesis was confirmed. Thus, the data in toto suggest that while p300-Wnt activity is an important effector of butyrate sensitivity in some CRC cell lines, other, p300-independent pathways influencing butyrate sensitivity must also exist.
Butyrate, a product of dietary fiber and a histone deacetylase inhibitor, induces apoptosis of colorectal cancer cells; this effect of butyrate is in part mediated by its ability to hyperactivate Wnt signaling, and may in part explain the preventive action of dietary fiber against colorectal cancer. However, the mechanisms by which Wnt hyperactivation promotes apoptosis are unknown. Inactivation of the retinoblastoma tumor suppressor occurs in some cancers and can lead to context-dependent cell proliferation or cell death/apoptosis. The function of retinoblastoma protein (Rb) in normal cells is modulation of cell cycle; inactivation of Rb allows for cell cycle progression and, hence, cell proliferation. Wnt signaling is upregulated in a variety of cancers, and deregulated Wnt signaling is a key initiating event in most cases of sporadic colorectal cancer. It has been shown that Wnt signaling activated by APC inactivation can synergize with the inactivation of Rb to induce apoptosis in a manner mediated by increased TORC1 activity, leading to induced metabolic and energy stress. Rb is typically not inactivated in colorectal cancer; however, Rb is phosphorylated and deactivated during cell cycle G1/S transition. This manuscript posits that it is during this time that butyrate/histone deacetylase inhibitor-induced Wnt hyperactivation induces apoptosis in colorectal cancer cells. Thus, the inactivation of Rb in cell cycle progression may synergize with Wnt hyperactivation to induce apoptosis in response to histone deacetylase inhibitors. The hypothesis is that hyperactivation of Wnt signaling enhances colorectal cancer cell apoptosis via the interaction between upregulated Wnt signaling and inactivated Rb during cell cycle progression. This paper discusses this hypothesis and offers initial experimental approaches for testing the hypothesis. A better understanding of how histone deacetylase inhibitors induce colorectal cancer cell apoptosis through hyperactivation of Wnt signaling, and of cross-talk between repression of cell cycle and induction of apoptosis that occurs with treatment with histone deacetylase inhibitors, can assist in the development of novel therapies for colorectal cancer.
Goodman and Gilman's The Pharmacological Basis of Therapeutics (GGPBT) has been a cornerstone in the education of pharmacists, physicians, and pharmacologists for decades. The objectives of this study were to describe and evaluate the 13th edition of GGPBT on bases including: (1) author characteristics; (2) recency of citations; (3) conflict of interest (CoI) disclosure; (4) expert evaluation of chapters. Contributors' (N = 115) sex, professional degrees, and presence of undisclosed potential CoI-as reported by the Center for Medicare and Medicaid's Open Payments (2013-2017)-were examined. The year of publication of citations was extracted relative to Katzung's Basic and Clinical Pharmacology (KatBCP), and DiPiro's Pharmacotherapy: A Pathophysiologic Approach (DiPPAPA). Content experts provided thorough chapter reviews. The percent of GGPBT contributors that were female (20.9%) was equivalent to those in KatBCP (17.0%). Citations in GGPBT (11.5 ± 0.2 years) were significantly older than those in KatBCP (10.4 ± 0.2) and DiPPAPA (9.1 ± 0.1, p < 0.0001). Contributors to GGPBT received USD 3 million in undisclosed remuneration (Maximum author = USD 743,718). In contrast, DiPPAPA made CoI information available. Reviewers noted several strengths but also some areas for improvement. GGPBT will continue to be an important component of the biomedical curriculum. Areas of improvement include a more diverse authorship, improved conflict of interest transparency, and a greater inclusion of more recent citations.
Organismal death does not immediately end gene expression. Studies of postmortem gene expression in zebrafish and mice and in the myocardium, liver, prostate, pericardial fluid, and blood of human cadavers have identified genes whose expression is increased after organismal death. Cancer can be considered a form of "un-death" since excessively proliferating cells are typically unusually resistant to apoptosis (programmed cell death), and are subject to strong selective pressure for "uncontrolled life." The changes in gene expression observed in organismal death, particularly in mammals (mice and humans), can be compared to that observed in human neoplasia, and the comparison of these expression patterns can inform us about human cancer. Here we present a hypothesis based on the following three tenets: (a) there will be distinct and opposing patterns of gene expression between the postmortem state and cancer with respect to key physiological outputs such as growth, apoptosis, invasion, and prognosis; (b) cancer cells considered more aggressive (e.g., derived from a metastasis and/or resistant to agents that suppress growth or induce apoptosis) will exhibit expression of relevant genes more unlike that of the postmortem condition while less aggressive neoplastic cells will exhibit gene expression more similar to the postmortem condition; and (c) targeting gene expression in cancer to produce a more postmortem-like pattern will promote less tumorigenic and less aggressive cell phenotypes. To evaluate components (a) and (b) of our hypothesis, we focus on previously published gene expression data from colorectal cancer (CRC) and colonic adenoma cells and compare that to postmortem expression data. This preliminary analysis in general supports our hypothesis, with more aggressive neoplastic cell types exhibiting gene expression patterns most unlike that found in the postmortem condition; this suggests that cancer and the postmortem condition represent opposing ends of a gene expression spectrum in the balance between life and death. Subsequently, we discuss the possibilities for further testing of the hypothesis, particularly for part (c), and we also discuss the possible implications of the hypothesis for cancer therapeutics.
Carcinogenesis/genetics , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic , Models, Biological , Neoplasms/genetics , Postmortem Changes , Animals , Butyrates/pharmacology , Cell Line, Tumor , Colonic Neoplasms/pathology , Death , Humans , Mice , Neoplasm Metastasis , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasms/metabolism , Neoplasms/therapy , Tissue Array Analysis
Secondary bile acids (BAs) and short chain fatty acids (SCFAs), two major types of bacterial metabolites in the colon, cause opposing effects on colonic inflammation at chronically high physiological levels. Primary BAs play critical roles in cholesterol metabolism, lipid digestion, and hostâ»microbe interaction. Although BAs are reabsorbed via enterohepatic circulation, primary BAs serve as substrates for bacterial biotransformation to secondary BAs in the colon. High-fat diets increase secondary BAs, such as deoxycholic acid (DCA) and lithocholic acid (LCA), which are risk factors for colonic inflammation and cancer. In contrast, increased dietary fiber intake is associated with anti-inflammatory and anticancer effects. These effects may be due to the increased production of the SCFAs acetate, propionate, and butyrate during dietary fiber fermentation in the colon. Elucidation of the molecular events by which secondary BAs and SCFAs regulate colonic cell proliferation and inflammation will lead to a better understanding of the anticancer potential of dietary fiber in the context of high-fat diet-related colon cancer. This article reviews the current knowledge concerning the effects of secondary BAs and SCFAs on the proliferation of colon epithelial cells, inflammation, cancer, and the associated microbiome.
Bile Acids and Salts/metabolism , Colon/metabolism , Fatty Acids, Volatile/metabolism , Lipid Metabolism , Animals , Butyrates/metabolism , Cell Proliferation , Colitis/etiology , Colitis/metabolism , Colitis/pathology , Colon/microbiology , Colonic Neoplasms/etiology , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Disease Susceptibility , Gastrointestinal Microbiome , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology
Deregulated Wnt signaling initiates most cases of colorectal cancer (CRC). Butyrate, a product of dietary fiber, hyperactivates Wnt signaling, resulting in induction of CRC cell apoptosis, which may in part explain the protective action of fiber. Nonsense mediated decay (NMD) of mRNAs containing premature stop codons (PTCs) affects tumorigenesis and upregulates Wnt signaling in human embryonic stem cells. However, it is unknown how NMD affects Wnt activity in CRC cells that exhibit constitutively activated Wnt signaling. We hypothesize that expression of genes that contain PTCs modulates Wnt signaling and response to butyrate in CRC cells. Amlexanox is a clinically utilized anti-allergic and anti-inflammatory drug that inhibits NMD and promotes PTC read-through. Therefore, Amlexanox is a relevant agent for assessing the role of NMD and PTC read-through in the response of CRC cells to butyrate. To test our hypothesis, we treated HCT-116 CRC cells with Amlexanox and determined effects on Wnt signaling levels, apoptosis, and response to butyrate. Amlexanox enhanced basal Wnt signaling levels; however, it repressed butyrate-induced Wnt signaling hyperactivation and suppressed apoptosis. To evaluate the contribution of NMD and altered expression of PTC-containing genes to these effects, we upregulated NMD by overexpression of up-frameshift protein 1 (UPF1), and observed effects opposite to these of Amlexanox (i.e., Wnt signaling hyperactivation by butyrate was enhanced and levels of apoptosis were increased). Our results support the possibility that altered expression of PTC-containing genes affects butyrate sensitivity of CRC cells.
Quantum-mediated effects have been observed in biological systems. We have previously discussed basis-dependent quantum selection as a mechanism for directed adaptive mutation, a process in which selective pressure specifically induces mutation in those genes involved in the adaptive response. Tumor progression in cancer easily lends itself to the adaptive evolutionary perspective, as the Darwinian combination of heritable variations together with selection of the better proliferating variants are believed to play a major role in multistep carcinogenesis. Adaptive mutation may play a role in carcinogenesis; accordingly, we propose that the principles of quantum biology are involved in directed adaptive mutation processes that promote tumor formation. In this paper, we discuss the intersection between quantum mechanics, biology, adaptive evolution, and cancer, and present general models by which adaptive mutation may influence neoplastic initiation and progression. As a potential theoretical and experimental model, we use colorectal cancer. Our model of "quantum cancer" suggests experiments to evaluate directed adaptive mutation in tumorigenesis, and may have important implications for cancer therapeutics.
Adaptation, Physiological/genetics , Carcinogenesis/genetics , Colorectal Neoplasms/genetics , Quantum Theory , DNA/genetics , DNA/metabolism , Humans , Isomerism , Mechanics , Mutation , Neoplasms/genetics , RNA/genetics , RNA/metabolism
Virulence is defined as the ability of a pathogen to cause morbidity and/or mortality in infected hosts. The relationship between virulence and transmissibility is complex; natural selection may promote decreased virulence to enhance host mobility and increase the probability for transmission, or transmissibility may be enhanced by increased virulence, leading to higher pathogen load and, in some cases, superior evasion from host defenses. An evolutionary trade-off exists between the ability of pathogens to maintain opportunities for long-term transmission via suppressed virulence and increased short-term transmission via enhanced virulence. We propose an analogy between transmissibility and virulence in microbial pathogens and in cancer. Thus, in the latter case, the outcome of invasive growth and metastasis is analogous to transmissibility, and virulence is defined by high rates of proliferation, invasiveness and motility, potential for metastasis, and the extent to which the cancer contributes to patient morbidity and mortality. Horizontal and vertical transmission, associated with increased or decreased pathogen virulence respectively, can also be utilized to model the neoplastic process and factors that would increase or decrease tumor aggressiveness. Concepts of soft vs. hard selection and evolutionary game theory can optimize our understanding of carcinogenesis and therapeutic strategies. Therefore, the language of transmissibility, horizontal vs. vertical transmission, selection, and virulence can be used to inform approaches to inhibit tumorigenic progression, and, more generally, for cancer prevention and treatment.
The signing of the National Cancer Act of 1971 by President Nixon marked the beginning of our war on cancer. More than 45 years later, the war is still going steady, with the enemy being almost as strong as in 1971. Furthermore, the increasing rates of obesity not only among adults, but among children and adolescents, are the likely cause for the 30-year trend of colon cancer (CC) becoming a disease of the younger population in the U.S. These trends, however, have not spurred the development of novel screening approaches for CC. Considering the need for a sensitive and non-invasive detection of early stage neoplastic lesions in the colon, we propose the development of a test based on a novel concept - the concept of induced biomarkers. The proposal is based upon our findings that the food additives propolis and gamma-cyclodextrin (gCD) (a) decrease the neoplastic burden in normal weight and obese ApcMin mice, a model of early stage intestinal neoplasia, and (b) elicit significant changes in the serum proteome in ApcMin mice. We posit that gCD and propolis induce the release of neoplasm-associated biomarkers in systemic circulation (e.g., metabolites, neoplastic, apoptotic, and immune response proteins), and these markers could be used to detect early stage intestinal neoplasms. Additional dietary bioactives may also elicit a complement of induced markers. The hypothesis could be ascertained by utilizing a mouse model, the Apc+/1638Nmice, as well as through human subject studies that integrate proteomics and metabolomics analyses. The concept of detecting inducible markers of colonic neoplasms is novel, and is substantiated by the significant physiological effects of gCD and propolis on neoplastic colonic cells in culture and on early neoplastic development in ApcMinmice. The long-term objective is to develop a minimally invasive method that detects early stage neoplastic development in the human colon.
Dietary fiber is linked to a reduced risk of colorectal cancer (CRC), and this protective activity is likely due to its fermentation product, butyrate. Dependent upon the hyperactivation of Wnt signaling, butyrate represses CRC cell growth and induces apoptosis. However, resistance to butyrate activity may allow for CRC development even in the context of relatively high fiber intake. We have previously determined that CRC cells resistant to butyrate are deficient in p300 expression. The histone acetylase p300 influences colonic cell signaling and physiology through effects on Wnt signaling. In this short research communication, we report that p300 knockout CRC cells exhibit butyrate resistance, and the re-introduction of p300 expression in p300 knockout CRC cells restores butyrate sensitivity. Microarray data on gene expression associated with butyrate sensitivity are presented and discussed.
