Too much of a good thing? Teamwork in medical education.

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.

Evaluating the medical curriculum: Bias, problems, solutions.

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.

Secondary Bile Acids and Short Chain Fatty Acids in the Colon: A Focus on Colonic Microbiome, Cell Proliferation, Inflammation, and Cancer.

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 host⁻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.

Vimentin, colon cancer progression and resistance to butyrate and other HDACis.

Dietary fibre protects against colorectal cancer (CRC) most likely through the activity of its fermentation product, butyrate. Butyrate functions as a histone deacetylase inhibitor (HDACi) that hyperactivates Wnt signalling and induces apoptosis of CRC cells. However, individuals who consume a high-fibre diet may still develop CRC; therefore, butyrate resistance may develop over time. Furthermore, CRC cells that are resistant to butyrate are cross-resistant to clinically relevant therapeutic HDACis, suggesting that the development of butyrate resistance in vivo can result in HDACi-resistant CRCs. Butyrate/HDACi-resistant CRC cells differ from their butyrate/HDACi-sensitive counterparts in the expression of many genes, including the gene encoding vimentin (VIM) that is usually expressed in normal mesenchymal cells and is involved in cancer metastasis. Interestingly, vimentin is overexpressed in butyrate/HDACi-resistant CRC cells although Wnt signalling is suppressed in such cells and that VIM is a Wnt activity-targeted gene. The expression of vimentin in colonic neoplastic cells could be correlated with the stage of neoplastic progression. For example, comparative analyses of LT97 microadenoma cells and SW620 colon carcinoma cells revealed that although vimentin is not detectable in LT97 cells, it is highly expressed in SW620 cells. Based upon these observations, we propose that the differential expression of vimentin contributes to the phenotypic differences between butyrate-resistant and butyrate-sensitive CRC cells, as well as to the differences between early-stage and metastatic colorectal neoplastic cells. We discuss the hypothesis that vimentin is a key factor integrating epithelial to mesenchymal transition, colonic neoplastic progression and resistance to HDACis.

Hypothesis: cell signalling influences age-related risk of colorectal cancer.

We propose that ageing is linked to colonic carcinogenesis through crosstalk between Wnt activity and signalling pathways related to ageing and senescence: progerin, klotho and mTOR. Mutations in the Wnt signalling pathway are responsible for the majority of colorectal cancers (CRCs); however, hyperactivation of Wnt signalling by butyrate, a breakdown product of dietary fibre, induces CRC cell apoptosis. This effect of butyrate may in part explain the protective action of fibre against CRC. Hutchinson-Gilford progeria syndrome is a premature ageing disorder caused by accumulation of the progerin protein; however, healthy individuals also produce progerin in the course of their normal ageing. Progerin activates expression of the Wnt inhibitors HES1 and TLE1. Thus, we hypothesize that with age, the increasing expression of progerin suppresses butyrate-mediated Wnt hyperactivation and apoptosis, leading to increased CRC risk. Wild-type klotho contributes to a significantly increased lifespan; however, Klotho gene variants differ significantly between newborns and elderly. Klotho inhibits basal Wnt signalling activity; thus, the protein may function as a tumour suppressor for CRC. However, similar to progerin, klotho variants associated with lifespan differences may repress butyrate-mediated Wnt hyperactivation, and thus increase the risk of CRC. Finally, mTOR signalling has also been linked to human ageing, and crosstalk between Wnt and mTOR signalling may influence colonic tumourigenesis. Understanding how progerin, klotho and mTOR link ageing with colonic neoplastic development may lead to novel preventive and therapeutic strategies against CRC associated with age.

Hypothesis: Cancer Hormesis and Its Potential for Cancer Therapeutics.

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.

Immunotherapy and Cannabis: A Harmful Drug Interaction or Reefer Madness?

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.

Hypothesis: functional age and onset of autosomal dominant genetic prion disease.

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.

Oncogenic and Receptor-Mediated Wnt Signaling Influence the Sensitivity of Colonic Cells to Butyrate.

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.

Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells.

Butyrate, a fermentation product of dietary fiber, inhibits clonal growth in colorectal cancer (CRC) cells dependent upon the fold induction of Wnt activity. We have developed a CRC cell line (HCT-R) that, unlike its parental cell line, HCT-116, does not respond to butyrate exposure with hyperactivation of Wnt signaling and suppressed clonal growth. PCR array analyses revealed Wnt pathway-related genes, the expression of which differs between butyrate-sensitive HCT-116 CRC cells and their butyrate-resistant HCT-R cell counterparts. We identified overexpression of Tcf3 as being partially responsible for the butyrate-resistant phenotype, as this DNA-binding protein suppresses the hyperinduction of Wnt activity by butyrate. Consequently, Tcf3 knockdown in HCT-R cells restores their sensitivity to the effects of butyrate on Wnt activity and clonal cell growth. Interestingly, the effects of overexpressed Tcf3 differ between HCT-116 and HCT-R cells; thus, in HCT-116 cells Tcf3 suppresses proliferation without rendering the cells resistant to butyrate. In HCT-R cells, however, the overexpression of Tcf3 inhibits Wnt activity, and the cells are still able to proliferate due to the higher expression levels of cell cycle factors, particularly those driving the G(1) to S transition. Knowledge of the molecular mechanisms determining the variable sensitivity of CRC cells to butyrate may assist in developing approaches that prevent or reverse butyrate resistance.

The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways.

Unlike the well-characterized nuclear function of the Notch intracellular domain, it has been difficult to identify a nuclear role for the ligands of Notch. Here we provide evidence for the nuclear function of the Notch ligand Delta-like 1 in colon cancer (CC) cells exposed to butyrate. We demonstrate that the intracellular domain of Delta-like 1 (Dll1icd) augments the activity of Wnt signaling-dependent reporters and that of the promoter of the connective tissue growth factor (CTGF) gene. Data suggest that Dll1icd upregulates CTGF promoter activity through both direct and indirect mechanisms. The direct mechanism is supported by co-immunoprecipitation of endogenous Smad2/3 proteins and Dll1 and by chromatin immunoprecipitation analyses that revealed the occupancy of Dll1icd on CTGF promoter sequences containing a Smad binding element. The indirect upregulation of CTGF expression by Dll1 is likely due to the ability of Dll1icd to increase Wnt signaling, a pathway that targets CTGF. CTGF expression is induced in butyrate-treated CC cells and results from clonal growth assays support a role for CTGF in the cell growth-suppressive role of butyrate. In conclusion, integration of the Notch, Wnt, and TGFbeta/Activin signaling pathways is in part mediated by the interactions of Dll1 with Smad2/3 and Tcf4.

Hypothesis: Mutations and Immunosurveillance in Obesity-Associated Colorectal Cancer.

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.

Hypothesis: Sam68 and Pygo2 mediate cell type-specific effects of the modulation of CBP-Wnt and p300-Wnt activities in Colorectal Cancer Cells.

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.

Multifactorial causation of early onset colorectal cancer.

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.

Further analysis of p300 in mediating effects of Butyrate in Colorectal Cancer Cells.

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.

Hypothesis: Retinoblastoma protein inactivation mediates effects of histone deacetylase inhibitor-induced Wnt hyperactivation in colorectal cancer cells.

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.

Modular Cre/lox system and genetic therapeutics for colorectal cancer.

The Cre/lox system is a powerful tool for targeting therapeutic effectors in a wide variety of human disorders. I review a Cre/lox Wnt-targeted system that has shown promise against Wnt-positive colorectal cancer cell lines. In addition to Wnt-specific targeting of cell death inducers, the modular nature of this gene therapy model system can be exploited by designing positive and negative feedback loops to either amplify or inhibit Wnt activity for experimental or therapeutic benefit. I discuss the structural components and performance parameters of the system, the implication of these findings with respect to cancer stem cells, as well as the general applicability of this system to any disorder characterized by differential gene expression. I also consider the issue of gene delivery as well as in vivo testing requirements necessary for the further characterization and development of this system.

Postmortem vs. neoplastic gene expression: Clues to cancer development and therapy.

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.

Quantum biology and human carcinogenesis.

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.