Nearly 3 out of 4 cancer patients undergoing chemotherapy suffer from loss of memory, attention or concentration. This range of cognitive deficiencies referred to as chemotherapy-induced cognitive impairment, chemobrain or chemofog severely hampers quality of life of patients undergoing treatment. Advanced neuroimaging analyses have identified structural white and gray matter damage following chemotherapy in patients treated for various types of cancer. Cognitive deficits associated with platinum-based therapeutics such as cisplatin have been observed for 5-10 years post-diagnosis. However, no United States Food and Drug Administration-approved therapeutic interventions are available to date.

Mitochondrial dysfunction, characterized by abnormal morphology, impaired bioenergetics, altered mitochondrial dynamics and mitochondrial DNA mutations, has emerged as an underlying mechanism of several pathologies, including neurodegenerative diseases, cerebral and cardiac ischemia , traumatic brain injury, spinal cord injury, cancer, and chemotherapy-induced cognitive impairment and peripheral neuropathy. Following cerebral ischemia, astrocytes donate their healthy mitochondria to ischemic neurons with dysfunctional mitochondria to maintain adequate mitochondrial function and survival.

Studies in the 1930s already showed that nasally administered bacteria can cross the nasal epithelium within minutes, indicating a paracellular route of entry.

In a recent study, Jenolyn F. Alexander, Cobi J. Heijnen and colleagues demonstrated that nasal administration of mesenchymal stem cells restores cisplatin-induced cognitive impairment in mice and their data indicated that these mesenchymal stem cells act by repairing neuronal mitochondrial damage. enter image description here

It appeared that autologous mesenchymal stem cells work as well as human mesenchymal stem cells in their mouse model. The concept of mitochondrial administration is also being considered the treatment of Parkinson's disease, cerebral and cardiac ischemia, cancer, diabetic nephropathy and spinal cord injuries and some clinical trials for evaluating the safety and efficacy of isolated mitochondria based therapies have also recently commenced.

These findings indicate that cisplatin-induced accumulation of mitochondrial p53 is the cause of the damage to brain mitochondria that leads to cognitive deficits in response to treatment with this chemotherapeutic. The authors recently showed that astrocytes donate their healthy mitochondria and rescue primary cortical neurons damaged by cisplatin in vitro.

Based on their above-mentioned findings that mitochondrial deficits underlie cisplatin-induced neuronal damage and cognitive deficits, and that healthy mitochondria can be taken up by damaged neurons, the scientists hypothesized that isolated mitochondria from healthy mesenchymal stem cells can be used to resolve cisplatin-induced cognitive deficits and the associated structural damage. This would provide an advantage from the perspective of safety because the scientists do not need donation of allogeneic intact cells.

Mice were intraperitoneally injected with cisplatin at 2.3 mg/kg for 5 consecutive days, followed by 5 days of rest and another 5 days of cisplatin injection. The two administrations of mitochondria on mice delivered nasally, completely restored within two weeks mice's executive functioning, spatial recognition and working memory previously impaired by cisplatin treatment. The entry of mesenchymal stem cells into the brain is facilitated by pretreatment of the nasal cavity with hyaluronidase. The scientists maintained the mitochondria in calcium-free mitochondrial respiration buffer until ready for nasal delivery when they were transferred to calcium-free PBS.

Within 30 min of nasal administration, the mitochondria were detectable in the meninges where they were predominantly internalized by macrophages. Within this 30 min, the mitochondria also arrived at the ventricles and choroid plexus, gaining access to the brain.

3 h after delivery, mitochondria were found distributed along the rostral migratory stream where they were internalized by GFAP+ cells. By this time the nasally administered mitochondria also reached the hippocampus. Evidently, these mitochondria that had entered the meninges and brain completely restored the cisplatin-induced white matter damage in the cingulate cortex, synaptic loss in the hippocampus, and the compromised synaptosome membrane integrity and structural mitochondrial defects in synaptosomes as observed 35 days after the second mitochondrial donation.

The scientists used mitochondria isolated from human mesenchymal stem cells in their mouse model for the primary purpose of being able to trace the administered mitochondria with a human-specific mitochondrial antibody.

One topic of concern usually raised with the administration of isolated mitochondria is the possibility that they may function as damage-associated molecular proteins (DAMPs) which could lead to neuroinflammation. However, the scientists did not see activation of inflammatory pathways in the hippocampal transcriptome using human mitochondria. Mitochondria lack many surface antigens including HLA-Class 1 antigens thereby exhibiting lower immunogenicity than mesenchymal stem cells. This is one advantage favoring the clinical translation of allogeneic donation of mitochondria over mesenchymal stem cells.

An important benefit of their approach is the nasal route of delivery. In case of central nervous system (CNS)-targeted delivery of therapeutics, intracranial administration poses serious risk of injury. Intravenous administration has the disadvantage that it may lead to accumulation in the lung and liver requiring high doses which may generate inflammatory reactions or other adverse effects. Systemic administration of therapeutics intended to reach the brain are also obstructed by the blood-brain and blood-cerebrospinal fluid (CSF) barriers. In contrast, the nasal route of delivery is simple, non-invasive and facilitates the delivery of therapeutics to the brain thereby reducing the amount of mitochondria required.

Questions are raised on the ability of isolated mitochondria to survive in high extracellular calcium levels upon administration and to generate sufficient energy to enter cells and continue to function after cellular uptake. Upon internalization, mitochondrial donation enhanced the bioenergetics of the damaged cells for at least 21 days.

It is still unknown how donated mitochondria repair damaged neuronal cells. Interactions between mitochondrial and nuclear genes are vital for fundamental cellular processes such as respiration, transcription and translation. The authors observed that the internalized mitochondria, in many instances were localized close to the nucleus (perinuclear), as if communicating with them. In the literature it has been suggested that donated mitochondria can fuse with mitochondria of damaged recipient cells and thereby repair the bioenergetic machinery or replenish mitochondrial DNA in the acceptor cell.

Although this might be true, it remains difficult to accept that the few mesenchymal stem cells-derived mitochondria can restore cellular respiration by physical fusion to the many acceptor cell mitochondria. It is more likely that the donated mitochondria activate a transcriptional program leading to enhanced Nrf2 signaling and subsequent recovery of host mitochondrial function by a host of antioxidants.

Their findings elucidate the therapeutic effects of nasally delivered mitochondria to resolve unmet needs in the treatment of cancer survivors with neurotoxicities and highlights its potential significance for clinical translation. It also provides promise for treatment of a range of cognitive and neuronal deficits warranting further investigation in large animal models.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Les Tumor Treating Fields (TTF) sont un type de thérapie par champ électromagnétique utilisant des champs électriques de faible intensité et de fréquence intermédiaire pour traiter le cancer. Le TTF de Novocure est approuvé aux États-Unis et dans l'UE pour le traitement du glioblastome (cancer du cerveau).

Environ un an et demi après avoir reçu l'approbation de la FDA comme traitement de première intention du mésothéliome, Novocure a obtenu le marquage CE pour sa thérapie Tumor Treating Fields en Europe.

Le système NovoTTF-100L, connu sous le nom d'Optune Lua aux États-Unis, sera également proposé en association avec une chimiothérapie à base de pémétrexed et de platine pour le traitement du mésothéliome pleural malin inopérable, avancé ou métastatique, un cancer du poumon rare lié à l'exposition à l'amiante.

entrez la description de l'image ici

Porté sur la poitrine comme un gros coussin, l'appareil délivre de l'énergie électromagnétique à la tumeur pour perturber la division et la réplication de cellules d'une certaine taille.

Le mésothéliome est un type de cancer qui se développe à partir du mésothélium, la fine couche de tissu qui recouvre de nombreux organes internes. La zone la plus fréquemment touchée est la muqueuse des poumons et de la paroi thoracique.

«Nous pensons que les récentes transactions de financement créent une flexibilité financière dans notre structure de capital afin de soutenir les investissements en cours destinés à stimuler la croissance à court terme et à dégager une valeur future à un coût du capital extrêmement favorable», a déclaré Ashley Cordova, directrice financière de Novocure.

Merck a signé il y a quelques mois un accord avec Novocure pour tester son anticorps Keytruda PD-1 en conjonction avec le traitement bioélectrique de Novocure.

Les deux sociétés prévoient de lancer une étude de phase 2 sur le cancer du poumon non à petites cellules avancé ou métastatique, mettant en avant le schéma médicament-plus-dispositif comme traitement potentiel de première intention.

Malgré l'obtention de l'approbation réglementaire, l'efficacité de cette technologie reste controversée parmi les experts médicaux.

Novocure's Tumor treating fields

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Tumor treating fields (TTF), is a type of electromagnetic field therapy using low-intensity, intermediate frequency electrical fields to treat cancer. Novocure's TTF is approved in the US and EU for the treatment of glioblastoma (Brain cancer).

About a year and a half after receiving approval from the FDA as a first-line treatment for mesothelioma, Novocure has secured a CE mark for its Tumor Treating Fields therapy in Europe.

The NovoTTF-100L system, known as Optune Lua in the U.S., will similarly be offered in combination with pemetrexed and platinum-based chemotherapy for the treatment of inoperable, advanced or metastatic malignant pleural mesothelioma, a rare lung cancer linked to asbestos exposure. enter image description here

Worn on the chest as a large pad, the device delivers electromagnetic energy to the tumor to disrupt the division and replication of cells of a certain size. The technology has also been approved for glioblastoma.

Mesothelioma is a type of cancer that develops from mesothelium, the thin layer of tissue that covers many of the internal organs. The most common area affected is the lining of the lungs and chest wall.

“We believe recent financing transactions create financial flexibility in our capital structure to support ongoing investments intended to drive near-term growth and unlock future value at an extremely favorable cost of capital,” said Novocure’s chief financial officer, Ashley Cordova.

Merck’s has signed up a few months ago to test its Keytruda PD-1 antibody alongside Novocure’s bioelectric treatment as well.

The two companies plan to launch a phase 2 study in advanced or metastatic non-small cell lung cancer, putting the drug-plus-device regimen forward as a potential first-line treatment.

Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.

Metastasis as a metabolic disease

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Metastase as a metabolic disease

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onward. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, more and more publications point toward metabolic aging as an important factor in cancer etiology and Ana Gomes, John Blenis, at Weill Cornell Medicine in New York, and their colleagues have made significant progress in this direction.

It is well known that many physiological processes are degraded or even severely altered in aging:
* lack of normal hepatic synthesis, excess of ammonia in the blood is a dangerous condition that may lead to brain injury and death. * gut microbiome dysbiosis, * development of insulin resistance, * impaired immune processes with persistent chronic neuro-inflammation, and persistent infectious.

Metabolic deregulation of the aged host may play a central role in the acquisition of aggressive properties that contribute to tumor progression.

Considering the growing body of evidence that cancer cell-extrinsic factors are key in modulating tumor progression, the scientists hypothesized that aging might produce a systemic environment that supports tumor progression and aggressiveness. To test this hypothesis, they cultured human cancer cells from 30 young and 30 old healthy donors.

Cells into young serum

Whereas the majority (25 out of 30) of cells treated with young donor serum (plasma from which the clotting proteins have been removed) maintained their epithelial morphology, cells treated with 25 out of the 30 old donors sera became mesenchymal, losing their polarity and displaying a spindle-shaped morphology. These phenotypes were independent of donor ethnicity, and resembled the epithelial-to-mesenchymal transition (EMT), a developmental process that is hijacked by cancer cells to acquire pro-metastatic properties.

Cells into old blood serum

Cells cultured with aged-donor serum displayed a pronounced loss of the epithelial marker E-cadherin and gain of the mesenchymal markers fibronectin and vimentin, in addition to increased expression of serpine1 and MMP2 (proteins associated with aggressive phenotypes). Moreover, the aged sera promoted resistance to two distinct and widely used chemotherapeutic drugs, carboplatin and paclitaxel.

Cancer cells into mice

To determine whether the cells treated with the old donor sera would also show heightened metastatic potential, the scientists treated breast cancer cells with human serum before injecting them into the tail veins of athymic mice. In contrast to the young sera, the aged sera potentiated the ability of the cells to colonize the lungs and form metastatic lesions.

Assessment of metabolites

Out of the 179 circulatory metabolites detected by targeted metabolomics, only 10 were altered at a statistically significant level. A pronounced decline in levels of glutathione, spermidine, glutamine and α-ketoglutarate was expected, considering their known or suggested roles in the ageing process. Notably, only three metabolites were consistently increased in the sera of aged donors: phosphoenolpyruvate, quinolinate and methylmalonic acid (MMA). * phosphoenolpyruvate is involved in glycolysis and gluconeogenesis * Quinolinic acid has a potent neurotoxic effect. * Methylmalonic acid (MMA), is converted into succinyl-CoA by methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor. In this way, it enters the Krebs cycle (a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins). 20–25% of patients over the age of 70 have elevated levels of MMA, but 25–33% of them do not have B12 deficiency. For this reason, MMA test is not routinely recommended in the elderly.

Which metabolite is responsible for the cells metastase-like behavior?

To test whether any of these three metabolites was responsible for inducing the pro-aggressive effects, the scientists treated cancer cells with each metabolite. Only MMA induced a complete pro-aggressive EMT-like phenotype with a decline in E-cadherin and a concurrent increase in fibronectin and vimentin. Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. Fibronectin may promote lung tumor growth/survival and resistance to therapy

Focus on MMA

The scientists measured the absolute concentration of MMA in the sera from all 60 donors. This analysis revealed that MMA levels were higher in the sera of the old donors (15–80 μM) than in that of the young donors (0.1–1.5 μM). Moreover, in the case of the ten outlier samples (five samples from old donors that did not induce EMT and five samples from young donors that did induce EMT), MMA levels consistently correlated with the phenotypes observed in cancer cells, supporting the idea that MMA is, at least in part, responsible for the observed age-related aggressive phenotypes.

Confirming that MMA is implicated in metastasis

To better understand the pro-aggressive properties of MMA, the scientists treated cells model for EMT studies with MMA. Concentrations of 1 mM and above were sufficient to induce an EMT-like phenotype and the expression of pro-aggressive proteins. Notably, the pro-aggressive effects of MMA were specific, as different acids with similar structures and pK a values did not induce the same complete phenotype under the specific conditions used.

MMA also induced resistance to carboplatin and paclitaxel, two common chemotherapy medication, and increased the migratory and invasive capacity of the cells, and promoted stem-like properties, as shown by an upregulation of CD44 and a decline in CD24.

Treatment of MDA-MB-231 cells in vitro with MMA was sufficient to robustly increase the ability of the cells to colonize the lungs of athymic mice in a concentration-dependent manner

MMA is not enough to induce metastasis

To assess whether another component of the serum could facilitate the entrance of MMA into cancer cells, the scientists depleted the old blood serum of lipids or of molecules larger than 3 kDa—two manipulations that should not affect the levels of polar metabolites such as MMA.

In both cases, the ability of the depleted old blood serum to induce pro-aggressive properties was abolished. Strikingly, both manipulations also caused a pronounced decrease in serum MMA levels.

MMA complexed with large lipidic structures

This suggests that the MMA has to be complexed with lipidic structures larger than 3 kDa in the serum in order to facilitate its entry into cancer cells.

To test this hypothesis, the scientists first complexed MMA with synthetic lipidic structures (lipofectamine) or with lipidic structures purified from fetal bovine serum (FBS). With both approaches, the concentration of MMA necessary to induce pro-aggressive properties was reduced to the levels similar to that of the old donor serum. Moreover, MMA complexed with lipidic structures from FBS produced a similar intracellular concentration of MMA within the same time frame as treatment with old donor serum.

MMA complexed with lipidic structures has similar properties to old blood serum

In support of this idea, treatment of cancer cells with lipidic structures isolated from old blood serum, but not from young serum, or isolated from young serum and loaded with MMA at concentrations similar to the ones found in the old blood serum, was sufficient to drive pro-aggressive properties. Conversely, depletion of lipidic structures from old blood serum resulted in a reduction in total serum MMA levels and was sufficient to abrogate the pro-aggressive phenotype. Orthotopic injections of MDA-MB-231 cells into the mammary fat pads of athymic mice with elevated circulatory MMA levels further demonstrated that circulatory MMA has a substantial role in tumor progression by promoting tumor growth and metastatic spread.


Aging promotes an increase in circulatory MMA, which in turn endows cancer cells with the properties necessary to migrate, invade, survive and thrive as metastatic lesions, which results in decreased cancer-associated survival. Although more in-depth studies are necessary to fully determine the scope of age-driven changes that contribute to the tumorigenic process, this study adds metabolic reprogramming to the complex relationship between aging and cancer.

A scientist from the Universitätsklinikum Erlangen, Heiko Bruns, pursues an innovative hypothesis on cancer metastases. He wrote his doctoral thesis on tuberculosis bacteria hidding in macrophages, and his postdoctoral thesis focused on the importance of macrophages in the context of cancer metastasis.

Macrophages are a type of white blood cell, which gobbles up and digests cell debris, foreign substances, microbes and cancer cells. Macrophages enter damaged tissues by the endothelium of blood vessels, a process known as extravasation. This process is very similar to what is currently thought to be the metastasis process.

enter image description here Classical conception of the metastasis process Source: doi: 10.1038 / nri3789

It is well known that macrophages can contribute to the growth and progression of cancers. Macrophages can also positively and negatively influence the results of anti-cancer treatments. Unfortunately some pathogens managed to lives inside those powerful macrophages. This allows them to escape from the immune system. This is the case with Mycobacterium tuberculosis or HIV.

Metastases are responsible for most of the deaths caused by cancer. Dr. Bruns believes that it is currently unclear how metastases form. So far, it has been assumed that they spread throughout the body via the lymphatic vessels and the bloodstream. But this mechanistic hypothesis cannot explain why some organs are preferably targeted in metastasis while other are relatively preserved. This was first discussed as the "seed and soil" theory by Stephen Paget in 1889. enter image description here Source Mikael Häggström via Wikipedia

Paradoxically, cancer patients with a high number of macrophages have a reduced life expectancy. In a mouse model, tumor growth almost stops when the macrophages where removed.

Heiko Bruns assumes that individual tumor cells are consumed by phagocytes, but are not necessarily eliminated by them. Instead, he suspects that tumor cells are using macrophages as "Trojans horses". They could thus escape detection and travel through the body to colonize other organs.

Dr. Heiko Bruns' idea was accepted into the 'Experiment! In search of bold research ideas' based on this unusual question. This idea received funding of 120,000 euros from the Volkswagen Foundation until the end of 2021.

Un scientifique de l'Universitätsklinikum Erlangen, Heiko Bruns, poursuit une hypothèse innovante sur les métastases cancéreuses. Il a rédigé sa thèse de doctorat sur la survie des bactéries de la tuberculose dans les macrophages, et sa thèse postdoctorale porte sur l'importance des macrophages dans le contexte de la métastase cancéreuse.

Les macrophages sont un type de globules blancs du système immunitaire, qui engloutit et digère les débris cellulaires, les substances étrangères, les microbes, les cellules cancéreuses. Les macrophages pénètrent dans les tissus endommagés par l'endothélium d'un vaisseau sanguin, un processus connu sous le nom d'extravasation de leucocytes. Ce processus ressemble beaucoup à celui qu’on pense être celui de la métastase.

enter image description here Classical conception of the metastasis process Source: doi: 10.1038 / nri3789

Il est bien connu que les macrophages peuvent contribuer à la croissance et à la progression des cancers. Les macrophages peuvent également influencer positivement et négativement les résultats des traitements anti-cancéreux. Cependant certains agents pathogènes réussissent à vivre même à l'intérieur des macrophages. Cela permet alors à l'agent pathogène d’échapper au système immunitaire. C'est le cas de Mycobacterium tuberculosis ou du VIH.

Les métastases sont responsables de la plupart des décès causés par le cancer. Le Dr Bruns pense qu'à l'heure actuelle, on ne sait pas vraiment comment les métastases se forment. Jusqu'à présent, on a supposé qu'elles se propageaient dans tout le corps via les vaisseaux lymphatiques et la circulation sanguine.

Paradoxalement, les patients cancéreux avec un nombre élevé de macrophages ont une espérance de vie diminuée. Un modèle de souris a démontré que la croissance tumorale s'arrête pratiquement lorsque les macrophages ont été retirés.

Heiko Bruns suppose que les cellules tumorales individuelles sont consommées par les phagocytes, mais ne sont pas nécessairement éliminées par ceux-ci. Au lieu de cela, il soupçonne que les cellules tumorales utilisent les macrophages comme «chevaux de Troie». Elles pourraient ainsi échapper à la détection et voyager à travers le corps pour coloniser d'autres organes.

L’idée du docteur Heiko Bruns a été acceptée au programme de financement «Expérience! A la recherche d'idées de recherche audacieuses 'sur la base de cette question inhabituelle. Il a reçu un financement de 120 000 euros de la Fondation Volkswagen jusqu'à fin 2021. Le projet devrait démarrer au printemps.

Le cancer se développe lorsque les cellules du corps acquièrent des mutations qui leur permettent de croître et de se diviser rapidement et de façon incontrôlable. À un certain stade de la maladie, ces cellules cancéreuses développent la capacité de se propager dans tout le corps. Ce processus de propagation, appelé métastase, est responsable de la plupart des décès liés au cancer chez l'homme, et pourtant il n’y a aucun traitement ciblant le processus de métastase.

De nombreuses études ont examiné des échantillons cliniques humains et/ou des lignées cellulaires dérivées de tumeurs pour discerner les mécanismes de métastases, et elles ont identifié des gènes spécifiques ainsi que le rôle du microenvironnement tumoral.

Il est à noter que des rapports anecdotiques suggèrent que des métastases peuvent survenir lors de circonstances qui favoriseraient l'inflammation telles que la chirurgie (Tohme et al., 2017) ou lors d'une infection (Smith et Kang, 2013). Les auteurs de l’étude suivante ont découvert que les protéines MYC et TWIST1 entraînent des métastases en activant un programme de transcription dans les cellules cancéreuses qui induit des cytokines qui à leur tour permettent le recrutement et la polarisation des macrophages.

enter image description here Cellules cancéreuses du foie avec des niveaux élevés de MYC (rouge) et TWIST1 se propageant dans un poumon infiltré de macrophages (verts) qui ont été convertis en un état favorable aux tumeurs. Crédit d'image: Nia Adeniji (CC BY 4.0)

Myc est un proto-oncogène qui est sur-exprimé dans certains cancers humains. Quand il est soumis à des mutations ou à une sur-expression, il stimule la prolifération des cellules et se conduit comme un oncogène.

TWIST1 est un facteur de transcription qui chez l'homme est codé par le gène TWIST1, il est impliqué dans le processus de métastase. L'inactivation de Twist par de petits ARN interférents ou une approche chimiothérapeutique a été démontrée in vitro. La thymoquinone, qui est isolé à partir de Nigella sativa (cumin noir), régule à la baisse le facteur de transcription TWIST1.

Cependant, à ce jour, il existe très peu de modèles in vivo où peut être étudiée la progression d'un cancer non métastatique vers un cancer métastatique. Les chercheurs ont donc généré un nouveau modèle de métastase de souris transgénique conditionnelle qui présente des caractéristiques complémentaires aux systèmes modèles existants.

Cet animal modèle développe systématiquement un carcinome hépatocellulaire, ou hépatocarcinome. C'est le type de cancer du foie primaire le plus fréquent chez les adultes et la cause de décès la plus fréquente chez les personnes atteintes de cirrhose Leur nouveau modèle leur a permis d’étudier les interactions tumeur-hôte lors d'une progression maligne chez un hôte immunocompétent. Dans leur modèle, plus de 90% des souris développent de façon prévisible des métastases extrahépatiques. Ils ont pensent que leur modèle a une pertinence générale pour tous les cancers humain et qu’il sera utile pour développer de nouvelles thérapies bloquant les métastases cancéreuses.

Sur cet animal modèle de la métastase, les chercheurs ont démontré que l'expression de MYC et de Twist1 est nécessaire pour déclencher la métastase. Ils ont découvert que MYC et Twist1 se lient aux promoteurs des gènes Ccl2 et Il13 humains et souris. MYC et Twist1 se coordonnent pour réguler un ensemble de cytokine, comprenant Ccl2 et Il13, qui sont tous deux nécessaires et suffisants pour provoquer des métastases.

Leurs résultats suggèrent que MYC et Twist1 peuvent contribuer aux métastases par un mécanisme transcriptionnel d'induction d'un cytokinome qui active les macrophages. Ils notent que leurs observations concordent avec une multitude de rapports selon lesquels l'immunité innée contribue aux métastases.

Ils proposent comme une explication générale possible de leurs résultats que la surexpression de MYC et TWIST1 dans une tumeur, active un programme embryonnaire d'activation des cellules immunitaires innées et d'invasion cellulaire. En effet MYC et TWIST1 coopèrent pendant l'embryogenèse. Il a également été démontré que ces deux facteurs de transcription modulent l'inflammation de manière transcriptionnelle pendant l'embryogenèse. Les changements de microenvironnement induits par l’inflammation, sont nécessaires pour permettre aux cellules mésodermiques de migrer vers leur destination.

Les chercheurs suggèrent que la thérapie personnalisée qui combine l'inhibition de CCL2 et d'IL13 est susceptible d'être efficace et que la stratification des patients en fonction de l'expression des cytokines pourrait aider à orienter le traitement.

Cancer develops when cells in the body acquire mutations that allow them to grow and divide quickly and uncontrollably. At some stage of the disease, these cancer cells develop the ability to spread throughout the body. This spreading process, called metastasis, is responsible for most cancer-related deaths in humans, yet there is no treatment targeting the metastasis process.

Numerous studies have examined human clinical samples and/or tumor-derived cell lines to discern the mechanisms of metastasis, and have identified specific genes as well as the role of the tumor micro-environment.

It should be noted that anecdotal reports suggest that metastases may occur under circumstances that would promote inflammation such as surgery (Tohme et al., 2017) or during an infection (Smith and Kang, 2013). The authors of the following study discovered that the proteins MYC and TWIST1 cause metastases by activating a transcription program in cancer cells which induces cytokines which in turn allow recruitment and polarization of macrophages.

enter image description here Liver cancer cells with high levels of MYC (red) and TWIST1 spreading into an infiltrated lung of macrophages (green) that have been converted to a tumor-friendly state. Image credit: Nia Adeniji (CC BY 4.0)

Myc is a proto-oncogene that is over-expressed in certain human cancers. When subjected to mutations or overexpression, it stimulates cell proliferation and behaves like an oncogene.

TWIST1 is a transcription factor which in humans is encoded by the TWIST1 gene and is involved in the metastasis process. Inactivation of Twist by small interfering RNAs or a chemotherapeutic approach has been demonstrated in vitro. Thymoquinone, which is isolated from Nigella sativa (black cumin), downregulates the transcription factor TWIST1.

However, to date, there are very few in vivo models in which the progression from non-metastatic cancer to metastatic cancer can be studied. The researchers therefore generated a new model of conditional transgenic mouse metastasis that has characteristics that are complementary to existing model systems. This model animal systematically develops hepatocellular carcinoma, or hepatocarcinoma.

It is the most common type of primary liver cancer in adults and the most common cause of death in people with cirrhosis Their new model has allowed them to study tumor-host interactions during malignant progression in an immunocompetent host. In their model, more than 90% of the mice predictably develop extrahepatic metastases. They believed that their model has general relevance for all human cancers and that it will be useful in developing new therapies that block cancer metastases.

In this animal model of metastasis, the researchers demonstrated that the expression of MYC and Twist1 is necessary to trigger metastasis. They discovered that MYC and Twist1 bind to promoters of the human and mouse Ccl2 and Il13 genes. MYC and Twist1 coordinate to regulate a set of cytokines, including Ccl2 and Il13, which are both necessary and sufficient to cause metastasis.

Their results suggest that MYC and Twist1 may contribute to metastases by a transcriptional induction mechanism of a cytokinoma which activates macrophages. They note that their observations are consistent with a multitude of reports that innate immunity contributes to metastasis.

They propose as a possible general explanation of their results that the overexpression of MYC and TWIST1 in a tumor, activates an embryonic program of activation of innate immune cells and of cellular invasion. Indeed MYC and TWIST1 cooperate during embryogenesis. These two transcription factors have also been shown to modulate inflammation transcriptionally during embryogenesis. The microenvironmental changes induced by inflammation are necessary to allow mesodermal cells to migrate to their destination.

Researchers suggest that personalized therapy that combines inhibition of CCL2 and IL13 is likely to be effective, and that stratification of patients by cytokine expression may help guide treatment.

Placental invasion into the maternal endometrium of the uterus has substantial similarities with the early spread of cancer in the stroma (the part of a tissue or organ with a structural or connective role). These similarities have inspired the hypothesis that trophoblasts (the continuous cell layer of fibroblasts that limit the egg, which became blastocyst at day 6 after fertilization) have developed the ability to invade the endometrium, leading to invasive placentation. Invasion of a specific type of trophoblast (extravillous trophoblast) in the maternal uterus is a vital step in the establishment of pregnancy. * Zephyris Source CC BY-SA 3.0, *

These mechanisms can be reactivated in cancer cells, leading to a predisposition to metastasis. It had been hypothesized (the ELI hypothesis) that cancer malignancy should be limited to placental mammals where invasive placentation first evolved. But there are several counterexamples.

In a recent article, the authors explore an alternative scenario in which stromal cells of the uterus evolved to resist or allow invasion, determining the outcome of placental invasiveness. The likelihood that changes in the stromal environment will lead to changes in cancer malignancy is reinforced by the fact that the molecular mechanisms used by cancer cells to metastasize are shared with other biological processes.

For example, mechanisms regulating gastrulation, wound healing, leukocyte extravasation, etc., are shared with both trophoblast and cancer invasion. This implies that invasive cancer cells use mechanisms that have evolved much earlier than placental invasion and, therefore, the evolution of invasive placentation per se can not be responsible for the origin of malignant cancer.

It is important to note, however, that the invasive nature of the placenta continued to evolve after its origin. Mammalian species differ in their tumorigenesis potential, as well as their vulnerability to cancer metastasis.

While the evolution resulted in an even higher degree of invasiveness in great apes, which includes humans, a complete loss of placental invasion has evolved in hoofed mammals, such as cows and horses and their parents, and these animals have lower malignancy rates for a variety of cancers.

In a recent review, Constanzo et al. presented compelling arguments for a model in which cancer progression in humans includes reactivation of the expression of embryonic genes normally controlling placental development and the development of the placenta. immune evasion.

For example, melanoma occurs in cattle and equines but remains largely benign; while it is very malign in the human. This correlates with the phenotype of the fetal-maternal interface (the degree of placental invasion during pregnancy). In particular, these results support that TGF-β secretion and high non-canonical WNT signaling in stromal cells are causal factors accounting for the high vulnerability of human stromal tissues to cancer invasion, at least in the case of melanoma .

Their data support the ELI hypothesis, suggesting that differences in stromal gene expression between species are critical in determining the degree of embryo implantation as well as stromal resistance to early cancer dissemination.


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L'invasion placentaire dans l'endomètre maternel de l'utérus présente des similitudes substantielles avec la dissémination précoce du cancer dans le stroma (la partie d'un tissu ou d'un organe ayant un rôle structurel ou conjonctif).

Ces similitudes ont inspiré l'hypothèse que les trophoblastes (la couche cellulaire continue formée de fibroblastes qui limite l'œuf, devenu blastocyste au 6e jour après la fécondation) ont développé la capacité d'envahir l'endomètre, conduisant à une placentation invasive. L'invasion d'un type spécifique de trophoblaste (trophoblaste extravilleux) dans l'utérus maternel est une étape vitale dans l'établissement de la grossesse. Source Zephyris CC BY-SA 3.0,

Ces mécanismes peuvent se réactiver dans les cellules cancéreuses, entraînant une prédisposition aux métastases. Il avait donc été fait l'hypothèse (nommée ELI) que la malignité cancéreuse devait être limitée aux mammifères placentaires où la placentation invasive a d'abord évolué. Mais il y a plusieurs contre-exemples.

Dans un article récent, les auteurs explorent un scénario alternatif dans lequel les cellules stromales de l'utérus ont évolué pour résister ou permettre l'invasion, déterminant le résultat de l'invasivité placentaire. La probabilité que l'évolution de l'environnement stromal entraîne l'évolution de la malignité cancéreuse est renforcée par le fait que les mécanismes moléculaires utilisés par les cellules cancéreuses pour métastaser sont partagés avec d'autres processus biologiques.

Par exemple, les mécanismes régulant la gastrulation, la cicatrisation des plaies, l'extravasation par les leucocytes, etc., sont partagés à la fois avec le trophoblaste et l'invasion du cancer. Cela implique que les cellules cancéreuses envahissantes utilisent des mécanismes qui ont évolué beaucoup plus tôt que l'invasion placentaire et, par conséquent, l'évolution de la placentation invasive en soi ne peut pas être responsable de l'origine du cancer malin.

Il est important de noter, cependant, que la nature invasive du placenta a continué d'évoluer après son origine. Les espèces de mammifères diffèrent par leur potentiel de tumorigenèse, ainsi que leur vulnérabilité aux métastases cancéreuses.

Alors que l'évolution a entraîné un degré d'envahissement encore plus élevé chez les grands singes, qui comprend les humains, une perte complète de l'invasion placentaire a évolué chez les mammifères à sabots, tels que les vaches et les chevaux et leurs parents, et ces animaux ont des taux de malignité inférieurs pour une variété des cancers.

Dans une revue récente, Constanzo et ses collaborateurs ont présenté des arguments convaincants pour un modèle où la progression du cancer chez l'homme comprend la réactivation de l'expression des gènes embryonnaires contrôlant normalement le développement du placenta et l'évasion immunitaire.

Par exemple, le mélanome survient chez les bovins et les équidés mais reste largement bénin; alors qu'il est très malin chez l'homme. Ceci est en corrélation avec le phénotype de l'interface fœtale-maternelle (le degré d'invasion placentaire pendant la grossesse).

En particulier, ces résultats soutiennent que la sécrétion de TGF-β et la signalisation WNT non canonique élevée dans les cellules stromales sont des facteurs causaux expliquant la forte vulnérabilité des tissus stromaux humains à l'invasion du cancer, au moins dans le cas du mélanome.

Leurs données soutiennent l'hypothèse ELI, suggérant que les différences d'expression génique stromale entre les espèces sont déterminantes pour déterminer le degré d'implantation de l'embryon ainsi que la résistance stromale à la dissémination précoce du cancer.


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