Your Risk for Colon Cancer

50,630:
this is the projected number of colorectal cancer (CRC) -related deaths for 2018 in the U.S. Only lung cancer-related deaths exceed this number.

How does CRC start? It begins as a benign growth – polyp / adenoma. The most frequent initiating mutation is in the APC gene, and less frequently - in the proteins beta-Catenin, Axin, and KRAS. Given sufficient time - approximately 10 years - and the right mutations (i.e., mutations that allow self-sufficiency in growth signaling, resistance to apoptosis, potential for unlimited growth, etc), malignancy develops.

Once the malignancy has established itself, cure is unlikely. Therefore, the best approach is this of prevention; the words of Ben Franklin are still valid:

… an ounce of prevention is worth a pound of cure…

The power of prevention is best understood when we look at the leading causes of death for the past 100 years. NEJM has published a great review that summarizes the ten leading causes of death in the U.S. since 1900. If we compare 1900 to 2010, we will find that the three biggest killers in 1900 were the gastrointestinal infections, pneumonia, and TB.  However, these were no longer the biggest killers in 2010 (the last year in the NEJM review).

How did we achieve that? Sanitation, better nutrition, vaccination, and antibiotics. Except for the antibiotics, the rest of the measures/changes were preventive.

Since the 1960s we have also seen reduction in heart disease-associated deaths due to prevention with medications that control blood pressure and cholesterol.

The lesson is that any significant victory against a disease is achieved through preventive strategies. There is no doubt in my mind that we will claim a significant victory against cancer, when we dedicate more financial resources to prevention. Cervical cancer is the perfect example how prevention through screening and vaccines reduces cancer deaths.

However, can we prevent colorectal cancer (CRC)? Obviously, screening is one answer; although quite invasive, colonoscopy detects early lesions. What else can we do? The American Institute for Cancer Research (AICR) has estimated that approximately 45% of all CRC cases can be prevented mostly through lifestyle changes. The institute has come up with five simple recommendations … that may slash the number of CRC cases by half! The problem with all these recommendations is that they require self-discipline.

The increased intake of fiber is one of the recommendations. Although the topic has been controversial for the past few decades, in 2003, two massive prospective epidemiological studies (one from Europe and one from the U.S.) concluded that fiber does protect against colon cancer: increasing the intake of fiber from 15 g to 35 g results in 40% decrease in risk.

Here is the summary of one of the studies:

Lancet 2003 May 3;361(9368):1496-501.Bingham SA:  
We prospectively examined the association between dietary fibre intake and incidence of colorectal cancer in 519978 individuals aged 25-70 years in ten European countries. Participants completed a dietary questionnaire in 1992-98 and were followed up for cancer incidence. …data for 1065 reported cases of colorectal cancer were included in the analysis. Dietary fibre in foods was inversely related to incidence of large bowel cancer (adjusted relative risk 0.75 [95% CI 0.59-0.95] for the highest versus lowest quintile of intake), the protective effect being greatest for the left side of the colon, and least for the rectum. After calibration with more detailed dietary data, the adjusted relative risk for the highest versus lowest quintile of fibre from food intake was 0.58 (0.41-0.85). No food source of fibre was significantly more protective than others, and non-food supplement sources of fibre were not investigated. In populations with low average intake of dietary fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40%.

In 2011, AICR and the continuous update project announced that the protective effect of fiber against colon cancer is upgraded from probable to convincing.

Asparagine Promotes Breast Cancer Metastasis

Asparagine influences breast cancer metastasis; abstract:

Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.

Ginseng Product

Another natural product against cancer that affects Wnt signaling; abstract:

BACKGROUND:

AD-2 (20(R)-dammarane-3b, 12b, 20, 25-tetrol; 25-OH-PPD) is a ginsenoside and isolated from Panax ginseng, showing anticancer activity against extensive human cancer cell lines. In this study, effects and mechanisms of 1C ((20R)-3b-O-(L-alanyl)-dammarane-12b, 20, 25-triol), a modified version of AD-2, were evaluated for its development as a novel anticancer drug.

METHODS:

MTT assay was performed to evaluate cell cytotoxic activity. Cell cycle and levels of reactive oxygen species (ROS) were determined using flow cytometry analysis. Western blotting was employed to analyze signaling pathways.

RESULTS:

1C concentration-dependently reduces prostate cancer cell viability without affecting normal human gastric epithelial cell line-1 viability. In LNCaP prostate cancer cells, 1C triggered apoptosis via Bcl-2 family-mediated mitochondria pathway, downregulated expression of mouse double minute 2, upregulated expression of p53 and stimulated ROS production. ROS scavenger, N-acetylcysteine, can attenuate 1C-induced apoptosis. 1C also inhibited the proliferation of LNCaP cells through inhibition on Wnt/β-catenin signaling pathway.

CONCLUSION:

1C shows obvious anticancer activity based on inducing cell apoptosis by Bcl-2 family-mediated mitochondria pathway and ROS production, inhibiting Wnt/β-catenin signaling pathway. These findings demonstrate that 1C may provide leads as a potential agent for cancer therapy.

Immune Memory And Neurological Disease

Innate immune memory in the brain shapes neurological disease hallmarks; abstract:

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

Cancer Stem Cells And Lipid Metabolism

Cancer stem cells seem to have an increased reliance on lipid metabolism, which can be a target for anti-cancer therapy.  I wonder if this has any implications for a ketogenic (high-fat) diet for cancer?  On the one hand, most cancer cells seem “glucose-addicted” so a low-carb, high-fat diet may be preferable.  On the other hand, if cancer stem cells rely more on fat, then will increased dietary fat be a problem?  This question needs to be investigated.  Abstract:

BACKGROUND:

Cancer stem cells (CSCs) or tumor-initiating cells (TICs) represent a small population of cancer cells with self-renewal and tumor-initiating properties. Unlike the bulk of tumor cells, CSCs or TICs are refractory to traditional therapy and are responsible for relapse or disease recurrence in cancer patients. Stem cells have distinct metabolic properties compared to differentiated cells, and metabolic rewiring contributes to self-renewal and stemness maintenance in CSCs.

MAIN BODY:

Recent advances in metabolomic detection, particularly in hyperspectral-stimulated raman scattering microscopy, have expanded our knowledge of the contribution of lipid metabolism to the generation and maintenance of CSCs. Alterations in lipid uptake, de novo lipogenesis, lipid droplets, lipid desaturation, and fatty acid oxidation are all clearly implicated in CSCs regulation. Alterations on lipid metabolism not only satisfies the energy demands and biomass production of CSCs, but also contributes to the activation of several important oncogenic signaling pathways, including Wnt/β-catenin and Hippo/YAP signaling. In this review, we summarize the current progress in this attractive field and describe some recent therapeutic agents specifically targeting CSCs based on their modulation of lipid metabolism.

CONCLUSION:

Increased reliance on lipid metabolism makes it a promising therapeutic strategy to eliminate CSCs. Targeting key players of fatty acids metabolism shows promising to anti-CSCs and tumor prevention effects.

Wnt Signaling, DKK3, and Alzheimer's Disease Models

More evidence of  dysfunctional Wnt signaling being involvedin the pathogenesis of Alzheimer’s disease (AD) is here, with the finding that the factor Dickkopf 3 (Dkk3) can alleviate AD in mouse models of the disease, through stimulating Wnt activity, and therefore Dkk3 can be a therapeutic target for AD. Abstract:

Dysfunctional Wnt signaling is associated with Alzheimer's disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD.

Protecting Normal Intestinal Cells From Chemotherapy: PUMA

How to spare normal intestinal cells in chemotherapy. Interfering with the p53-PUMA axis by repressing PUMA can protect the normal cells while leaving p53-mediated killing of cancer cells intact.  This presumably is for p53 wild-type cells.  Many cancers lose p53 expression and for those this would likely be irrelevant.  Abstract:

The gastrointestinal (GI) epithelium is the fastest renewing adult tissue and is maintained by tissue-specific stem cells. Treatment-induced GI side effects are a major dose-limiting factor for chemotherapy and abdominal radiotherapy and can decrease the quality of life in cancer patients and survivors. p53 is a key regulator of the DNA damage response, and its activation results in stimulus- and cell type-specific outcomes via distinct effectors. We demonstrate that p53-dependent PUMA induction mediates chemotherapy-induced intestinal injury in mice. Genetic ablation of Puma, but not of p53, protects against chemotherapy-induced lethal GI injury. Blocking chemotherapy-induced loss of LGR5+ stem cells by Puma KO or a small-molecule PUMA inhibitor (PUMAi) prevents perturbation of the stem cell niche, rapid activation of WNT and NOTCH signaling, and stem cell exhaustion during repeated exposures. PUMAi also protects human and mouse colonic organoids against chemotherapy-induced apoptosis and damage but does not protect cancer cells in vitro or in vivo. Therefore, targeting PUMA is a promising strategy for normal intestinal chemoprotection because it selectively blocks p53-dependent stem cell loss but leaves p53-dependent protective effects intact.

Colorectal Cancer And Bacterial Colonization

Colonization by a specific bacterial species is “strongly associated” with colorectal cancer; whether this is cause or effect – or both – remains to fully determined.  This study suggests that it is at least effect – conditions leading to cancer development, including deregulation of Wnt signaling, favor the colonization at the expense of other bacterial species.  It is of course also possible that these “bad” (?) bacteria, once established, then affect the further progression of the cancer.  At the very least, their presence is a sign something is not right.  Abstract:

Colonization by Streptococcus gallolyticus subsp. gallolyticus (SGG) is strongly associated with the occurrence of colorectal cancer (CRC). However, the factors leading to its successful colonization are unknown, and whether SGG influences the oncogenic process or benefits from the tumor-prone environment to prevail remains an open question. Here, we elucidate crucial steps that explain how CRC favors SGG colonization. By using mice genetically prone to CRC, we show that SGG colonization is 1,000-fold higher in tumor-bearing mice than in normal mice. This selective advantage occurs at the expense of resident intestinal enterococci. An SGG-specific locus encoding a bacteriocin ("gallocin") is shown to kill enterococci in vitro. Importantly, bile acids strongly enhance this bacteriocin activity in vivo, leading to greater SGG colonization. Constitutive activation of the Wnt pathway, one of the earliest signaling alterations in CRC, and the decreased expression of the bile acid apical transporter gene Slc10A2, as an effect of the Apc founding mutation, may thereby sustain intestinal colonization by SGG. We conclude that CRC-specific conditions promote SGG colonization of the gut by replacing commensal enterococci in their niche.

Machine whisperers

Do you know what your doctor will be specializing in soon? She might be learning how to interact with machines, not with people. It is predicted that in the future, the doctors will have to adjust to a healthcare environment that is dominated by artificial intelligence (AI).

According to the article Medical Education Must Move From the Information Age to the Age of Artificial Intelligence by Steven A. Wartman, MD, PhD, and C. Donald Combs, PhD, here are the changes that we will encounter soon:

1. Health care will be provided in many locations since data storage/processing will be accessible in real time everywhere.

2. Health care will be provided by teams of physicians, nurses, social workers, therapists, home health aides, support groups, families, etc.

3. Health care will be guided by large data sets and artificial intelligence.

4. Physicians will be cognitively and physically outperformed by devices.



To understand some of the first applications of AI in clinical practice, watch this Google talk:
 


There are many aspects of the AI - dominated medicine that can be discussed; however, I am thinking about three imminent consequences.

First, the medical education would no longer focus on basic sciences. Medical education will prepare the future doctors to work with the machines and AI, which will churn out analyses of gigantic data sets. Decisions on life and death will be taken based upon algorithms. The docs will become “machine whisperers”. 

Second, docs will mostly manage machines and teams to deliver various aspects of the patient care. The landscape of educators in medical schools will change from this of basic and clinical scientists/practitioners to this dominated by specialists in informatics and programmers.

Third, since the teaching of basic sciences knowledge will dwindle, the medical doctors might not be able to replicate the logical sequence of differential diagnosis. They will know how to work with the machines and AI, but they would be in the dark about the basic reasons behind the causes for pathological conditions and proposed treatments. After all, such information would be accessible immediately through technology, as the docs need it. 

This situation reminds me of a conversation I had more than 20 years ago in my research lab. As a PhD student, I loved talking to one of my senior researchers. She had more than 30 years of experience and had been one of the first laboratory technicians applying molecular biology approaches in cancer research. She knew how to isolate RNA and DNA, she prepared the perfect protein lysates. She knew why each step in a protocol was included, why particular chemicals were used, in what proportions, etc. At the time, we were discussing the new kits that made the life of all researchers much easier. The kits came with protocols that specified, “use 5 ml of solution A, mix for two minutes, then add 20 ml of solution B”. Most of us, the students, blindly followed the directions without any understanding of the guiding principles behind the procedures. We did not know what solutions A and B were, why we had to mix them and why timing was crucial...

Could the same intellectual and informational blindness affect our medical doctors? I believe, it can. They may become no more than “machine whisperers” and managers of teams. Laboratory/clinical research, individual creativity and logic might be abandoned little by little. The trend has already started. Consolidation of research allows only the biggest and financially strongest players to stay in the game (think of whom the big investors fund today). There is no longer room and opportunities for the smaller, less financed schools and researchers to continue exploring new ideas. The level of creativity and initiative will change, as less and less individuals are allowed to develop and practice their imagination and innovation skills.

For a fictional interpretation of how AI and humanity may interact check out this post.