Here, we review certain recent advances in oxidative stress and tumor metabolism, which are related to understanding the contributions of the microenvironment in promoting tumor growth and ...metastasis. In the early 1920s, Otto Warburg, a Nobel Laureate, formulated a hypothesis to explain the "fundamental basis" of cancer, based on his observations that tumors displayed a metabolic shift toward glycolysis. In 1963, Christian de Duve, another Nobel Laureate, first coined the phrase auto-phagy, derived from the Greek words "auto" and "phagy," meaning "self" and "eating."
Now, we see that these two ideas (autophagy and aerobic glycolysis) physically converge in the tumor stroma. First, cancer cells secrete hydrogen peroxide. Then, as a consequence, oxidative stress in cancer-associated fibroblasts drives autophagy, mitophagy, and aerobic glycolysis.
This "parasitic" metabolic coupling converts the stroma into a "factory" for the local production of recycled and high-energy nutrients (such as L-lactate)-to fuel oxidative mitochondrial metabolism in cancer cells. We believe that Warburg and de Duve would be pleased with this new two-compartment model for understanding tumor metabolism. It adds a novel stromal twist to two very well-established cancer paradigms: aerobic glycolysis and autophagy.
Undoubtedly, these new metabolic models will foster the development of novel biomarkers, and corresponding therapies, to achieve the goal of personalized cancer medicine. Given the central role that oxidative stress plays in this process, new powerful antioxidants should be developed in the fight against cancer.
We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells ...secrete hydrogen peroxide (H2O2), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the "Reverse Warburg Effect," as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immuno-staining of human breast cancer tissue microarrays (TMAs; > 180 triple-negative patients) to directly assess the prognostic value of the "Reverse Warburg Effect." MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis, and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (< 18% survival at 10 y post-diagnosis). In contrast, patients with absent stromal MCT4 expression (score = 0), had 10-y survival rates of ~97% (p-value < 10
−32
). High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 (p-value < 10
−14
), a known marker of early tumor recurrence and metastasis. In fact, the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients, consistent with the goal of individualized risk-assessment and personalized cancer treatment. However, epithelial MCT4 staining had no prognostic value, indicating that the "conventional" Warburg effect does not predict clinical outcome. Thus, the "Reverse Warburg Effect" or "parasitic" energy-transfer is a key determinant of poor overall patient survival. As MCT4 is a druggable-target, MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers. Similarly, we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors (such as, AR-C155858, AR-C117977, and AZD-3965).
Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to ..."feed" adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. These data are consistent with the "reverse Warburg effect," which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, "energy transfer" or "metabolic-coupling" between the tumor stroma and epithelial cancer cells "fuels" tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCT inhibitors.
The intestinal epithelium has a high rate of cell turnover, which is regulated by stem cells located near the base of crypts. We aimed to investigate stem cell-dependent characteristics of cell ...proliferation, apoptosis, and crypt size in terminal ileum and different regions of the colon.
Mice were studied under steady-state conditions and after radiation-induced stem cell apoptosis. Percentage of proliferating or apoptotic cells at a particular cell position (cp) along the crypt axis was expressed as labeling or apoptotic index.
Under steady-state conditions: crypt size was smallest in the ascending colon. In contrast to other regions of the colon, the distribution profile of proliferating cells in ascending colon showed some similarity to that in the terminal ileum. Postirradiation: apoptotic cells were prominent at the bottom of the crypt of mid- and descending colon but in the ascending colon, they were seen with similar frequency from cp 1 to 4. During regeneration, a constant proliferative capacity was seen above Paneth cells in the terminal ileum. In the ascending (but not mid- or descending) colon, the profile of proliferating cells over the first 4 days after irradiation showed a similarity to that in the terminal ileum.
Profiles of proliferating epithelial cells (under steady-state conditions and postirradiation) and apoptotic cells (postirradiation) suggest similarities in the location of stem cells in the ascending colon and terminal ileum.
Stem cells have been identified in two locations in small intestinal crypts; those intercalated between Paneth cells and another population (which retains DNA label) are located above the Paneth cell ...zone, at cell position 4. Because of disadvantages associated with the use of DNA label, doxycycline-induced transient transgenic expression of histone 2B (H2B)-green fluorescent protein (GFP) was investigated. H2B-GFP-retaining putative stem cells were consistently seen, with a peak at cell position 4, over chase periods of up to 112 days. After a 28-day chase, a subpopulation of the H2B-GFP-retaining cells was cycling, but the slow cycling status of the majority was illustrated by lack of expression of pHistone H3 and Ki67. Although some H2B-GFP-retaining cells were sensitive to low-dose radiation, the majority was resistant to low- and high-dose radiation-induced cell death, and a proportion of the surviving cells proliferated during subsequent epithelial regeneration. Long-term retention of H2B-GFP in a subpopulation of small intestinal Paneth cells was also seen, implying that they are long lived. In contrast to the small intestine, H2B-GFP-retaining epithelial cells were not seen in the colon from 28-day chase onward. This implies important differences in stem cell function between these two regions of the gastrointestinal tract, which may have implications for region-specific susceptibility to diseases (such as cancer and ulcerative colitis), in which epithelial stem cells and their progeny are involved.
Cardiovascular disease is a common cause of morbidity and mortality in pregnant women. Arrhythmias are common complications during pregnancy; however, the data are limited. Our goal was to ...characterize the epidemiology, clinical presentation, and impact of cardiac arrhythmias on maternal–fetal outcomes.
A prospective cohort study from the Colombian Registry of Pregnancy and Cardiovascular Disease was carried out from 2016 to 2019. All patients with tachyarrhythmia or bradyarrhythmia and a minimum follow-up of six months after delivery were included. The primary outcome was a composite of cardiac events defined as pulmonary edema, symptomatic sustained arrhythmia requiring specific therapy, stroke, cardiac arrest, or maternal death. Secondary outcomes were other cardiac, neonatal, and obstetric events.
Arrhythmias were the most common cause of referral to our dedicated cardio-obstetric clinic. A total of 92 patients were included, mean age 27±6 years; 8.7% had previous structural heart disease, and cardiology consultation was delayed in 79.4%. The most common arrhythmias were premature ventricular contractions (33%) and paroxysmal reentrant supraventricular tachycardias (15%); 11 patients (12%) had cardiac implantable electronic devices. Cardiac events occurred in 18.4% of patients, obstetric events occurred in 6.5%, and one caesarean was indicated in the context of symptomatic severe mitral stenosis. Adverse neonatal outcomes were observed in 24.3% of newborns.
Arrhythmias were the most common cause of referral to a dedicated cardio-obstetric clinic; most had a benign course. Adverse maternal cardiovascular outcomes were significant and there was a high rate of obstetric and neonatal adverse events, underlining the importance of multidisciplinary care.
As doenças cardiovasculares são uma causa comum de morbidade e mortalidade em mulheres grávidas. As arritmias são complicações comuns durante a gravidez; no entanto, há dados limitados. O nosso objetivo foi caracterizar a epidemiologia, a apresentação clínica e os desfechos das arritmias cardíacas nos desfechos materno-fetais.
Coorte prospetiva do Registo de Gravidez e Doenças Cardiovasculares (REMEC) foi realizada entre 2016 e 2019. Foram incluídas todas as pacientes com taquiarritmia ou bradiarritmia e seguimento mínimo de seis meses após o parto. O desfecho primário foi um composto de eventos cardíacos definidos como edema pulmonar, arritmia sustentada sintomática que requer terapia específica, acidente vascular cerebral, parada cardíaca ou morte materna; os desfechos secundários incluíram outros eventos cardíacos, neonatais e obstétricos.
Foram incluídas 92 pacientes, a média de idade foi de 27 (±6) anos, 8,7% apresentavam cardiopatia estrutural prévia e 79,4% tiveram atraso na consulta de cardiologia. As arritmias mais comuns foram contrações ventriculares prematuras (33%) e taquicardias supraventriculares reentrantes paroxísticas (15%); 11 pacientes (12%). Tinham dispositivos cardíacos eletrónicos implantáveis. O eventos cardíacos estiveram presente em 18,4%. Intercorrências obstétricas ocorreram em 6,5% das pacientes, sendo indicada uma cesariana no contexto de estenose mitral grave sintomática. Desfechos neonatais adversos estiveram presentes em 24,3% dos recém-nascidos.
As arritmias são a causa mais comum de encaminhamento para uma clínica cardio-obstétrica dedicada; a maioria delas tem um curso benigno. Desfechos cardiovasculares maternos adversos foram significativos e uma taxa importante de eventos adversos obstétricos e neonatais, destacando a importância do cuidado multidisciplinar.
Cigarette smoke has been directly implicated in the disease pathogenesis of a plethora of different human cancer subtypes, including breast cancers. The prevailing view is that cigarette smoke acts ...as a mutagen and DNA damaging agent in normal epithelial cells, driving tumor initiation. However, its potential negative metabolic effects on the normal stromal microenvironment have been largely ignored. Here, we propose a new mechanism by which carcinogen-rich cigarette smoke may promote cancer growth, by metabolically "fertilizing" the host microenvironment. More specifically, we show that cigarette smoke exposure is indeed sufficient to drive the onset of the cancer-associated fibroblast phenotype via the induction of DNA damage, autophagy and mitophagy in the tumor stroma. In turn, cigarette smoke exposure induces premature aging and mitochondrial dysfunction in stromal fibroblasts, leading to the secretion of high-energy mitochondrial fuels, such as L-lactate and ketone bodies. Hence, cigarette smoke induces catabolism in the local microenvironment, directly fueling oxidative mitochondrial metabolism (OXPHOS) in neighboring epithelial cancer cells, actively promoting anabolic tumor growth. Remarkably, these autophagic-senescent fibroblasts increased breast cancer tumor growth in vivo by up to 4-fold. Importantly, we show that cigarette smoke-induced metabolic reprogramming of the fibroblastic stroma occurs independently of tumor neo-angiogenesis. We discuss the possible implications of our current findings for the prevention of aging-associated human diseases and, especially, common epithelial cancers, as we show that cigarette smoke can systemically accelerate aging in the host microenvironment. Finally, our current findings are consistent with the idea that cigarette smoke induces the "reverse Warburg effect," thereby fueling "two-compartment tumor metabolism" and oxidative mitochondrial metabolism in epithelial cancer cells.
Introducción: la falla cardiaca con fracción de eyección reducida dispone de un arsenal terapéutico cada vez más amplio por lo que se requiere refinar las indicaciones de cada una de ellas. Métodos: ...se realizó una revisión sistemática siguiendo las directrices de Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), para actualizar la búsqueda sistemática realizada para el desarrollo de la "Guía de Practica Clínica para la prevención, diagnóstico, tratamiento y rehabilitación" (GPC) del Ministerio de Salud de Colombia. Resultados: se detectaron seis ensayos clínicos nuevos que modifican sustancialmente las recomendaciones principales de la GPC. Los antagonistas del receptor de angiotensina combinado con inhibidor de neprilisina (ARNI), los inhibidores del cotransportador sodio glucosa-2 (ISGLT-2), los betabloqueadores y los antagonistas mineralocorticoides (ARM) se convierten en el núcleo principal del tratamiento de los pacientes con falla cardiaca con fracción de eyección reducida. Otras opciones terapéuticas deben ser consideradas después de iniciar y titular las dosis de estos cuatro medicamentos. Discusión: el esquema práctico propuesto, como núcleo central con cuatro estrategias terapéuticas fundamentales, dada la robustez de los resultados de los ensayos en que fueron evaluados, permitirá mejorar el tratamiento de los pacientes con falla cardiaca e incluir en forma escalonada con el uso de otras alternativas, graficado como órbitas, para impactar otros desenlaces individuales. (Acta Med Colomb 2021; 46. DOI: Palabras clave: falla cardiaca, epidemiología, tratamiento, mortalidad. Introduction: heart failure with reduced ejection fraction has a growing therapeutic arsenal. Thus, the indications for each therapy must be refined. Methods: a systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, to update the systematic search performed in the development of the "Clinical Practice Guidelines for Prevention, Diagnosis, Treatment and Rehabilitation" (CPG) of the Colombian Ministry of Health. Results: six new clinical trials were found which substantially modify the main recommendations of the CPG. Angiotensin receptor antagonists combined with neprilysin inhibitors (ARNI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, betablockers and mineralocorticoid receptor antagonists (MRA) are now the main core of treatment for patients with heart failure with reduced ejection fraction. Other therapeutic options should be considered after beginning and titrating the doses of these four medications. Discussion: given the robustness of the evaluating studies, the proposed practical scheme, as the central core with four fundamental therapeutic strategies, will improve the treatment of patients with heart failure and allow the stepwise inclusion of other alternatives, plotted as orbits, to impact on other individual outcomes. (Acta Med Colomb 2021; 46. DOI: Keywords: heart failure, epidemiology, mortality.
El objetivo de este artículo fue iniciar un diálogo entre historia y escatología desde la experiencia del sufrimiento humano en Dios. Por tanto, se abordará el método dialéctico para establecer una ...reflexión hermenéutica que permita comprender el sufrimiento del presente desde la fuerza del pretérito y el compromiso con el futuro. Para ello, será fundamental el pensamiento teológico de Johann Baptist Metz y de otros autores, quien desde su propuesta teológico-política y desde la memoria provocadora en el contexto de un mundo altamente globalizado reivindica el problema de la teodicea desde la experiencia del hombre que sufre y reclama a Dios el fin inminente de este. Ahora bien, dentro del mundo académico de la teología, se han realizado varios esfuerzos por estructurar una teología política que mire al mundo, pues la fe cristiana es fe con los ojos abiertos, pero no ha obtenido la recepción necesaria dentro del mundo académico ni en el marco eclesial formal. Los esfuerzos realizados después del auge del Concilio Vaticano II despertaron en 1968 un clamor del oprimido, del pobre y del sufriente, que aún se desconoce tanto en el ámbito latinoamericano como en el europeo. En consecuencia, nace este diálogo entre historia y escatología, en el cual se abordará, primero, la singularidad de la fe en la esfera de un nuevo nominalismo; segundo, la secularización del fruto del hombre burgués ilustrado y la modernidad, y, finalmente, se esbozará concretamente la relación entre memoria y esperanza en el contexto de Auschwitz.
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