MIC-1

mise à jour, l'Article date de octobre 2014

MIC-1/GDF15 is a member of the TGF-β superfamily that plays role in the pathogenesis of a number of disease processes including cancer. MIC-1/GDF15 is overexpressed in prostate cancer (PCa) and other common malignancies and its expression is linked to cancer outcome. We have evaluated the effect of MIC-1/GDF15 overexpression and deletion on the evolution of PCa in transgenic TRAMP prostate cancer prone mice. We generated two syngeneic TRAMP mouse lines, one that overexpresses MIC-1/GDF15 (TRAMP
fmsmic-1) and the other that lacks MIC-1/GDF15 expres​sion(TRAMPMIC-/-). We then compared their survival, prostate tumor size, histopathological grade and extent of metastases with that of TRAMP
mice. TRAMPMIC-/- had 4-5 weeks shorter survival but had larger prostate tumors at necropsy than TRAMP mice. However, TRAMP fmsmic-1 mice had 7 weeks longer survival, smaller genitourinary tumors and lower PCa grades but had higher incidence of metastasis than TRAMP mice. To confirm this, we compared metastasis of TC1-T5, an androgen independent TRAMP cell line that lacks MIC-1/GDF15 expression, byinjecting intravenously into MIC-1/GDF15 overexpressing (MIC-1 fms) and syngeneic WT C57BL/6 mice. We observed a significantly higher number of TC1-T5 lung tumor colonies in MIC-1fms mice than WT C57BL/6 mice. Our studies suggest that MIC-1/GDF15 plays a different role in early compared to advanced cancer: Early in disease it may protect from and slows the growth of PCa. However, with advancing disease,MIC-1/GDF15 overexpression may promote metastases. As all cancer treatments induce MIC-1/GDF15 expression and metastasis is the major cause of cancer treatment failure, these results may have a direct impact on patient care.
---

MIC-1 / GDF15 est un membre de la superfamille TGF-β qui joue un rôle dans la pathogenèse d'un certain nombre de processus de maladies y compris le cancer. MIC-1 / GDF15 est surexprimé dans le cancer de la prostate (CaP) et dans d'autres tumeurs malignes courantes et son expression est liée à l'évolution du cancer.

Nous avons évalué l'effet de la surexpression de MIC-1 / GDF15 et de sa suppression sur l'évolution du cancer du cancer de la de la souris TRAMP transgénique. Nous avons généré deux lignées de souris TRAMP syngénique, celle qui surexprime MIC-1 / GDF15 (TRAMP fmsmic-1) et l'autre qui manque de MIC-1 / expression de GDF15 (TRAMPMIC - / -).

Nous avons ensuite comparé leur survie, et la  taille de la tumeur de la prostate, le grade histologique et l'étendue des métastases avec celle des souris TRAMP. TRAMPMIC - / - avaient une survie de 4-5 semaines plus courte mais a eu de plus grandes tumeurs de la prostate à l'autopsie que les souris TRAMP. Cependant, les souris TRAMP fmsmic-1 ont eu une survie 7 semaines de plus, les tumeurs génito-urinaires CaP étaient plus petits et plus faibles, mais il a eu une incidence plus élevée de métastases que les souris TRAMP.

Pour confirmer cela, nous avons comparé avec les métastases du TC1-T5, une lignée de cellules TRAMP indépendante des androgènes qui manque de MIC-1 / GDF15, en injectant par voie intraveineuse dans des souris (MIC-1 FMS) et syngéniques WT C57BL/6 surexprimant MIC-1 / GDF15.

Nous avons observé un nombre significativement plus élevé de colonies tumorales TC1-T5 au poumon de souris micro-1fms et WT C57BL / 6. Nos études suggèrent que MIC-1 / GDF15 joue un rôle différent au début par rapport à un cancer avancé: Au début de la maladie, il peut protéger contre la croissance du cancer de la prostate et la ralentir. Cependant, avec la maladie qui a progressé, la surexpression de MIC-1 / GDF15 peut favoriser les métastases. Comme tous les traitements contre le cancer induisent l'expression MIC-1 / GDF15 et que la métastase est la principale cause de l'échec du traitement du cancer, ces résultats peuvent avoir un impact direct sur les soins aux patients.

(Nov. 6, 2007) — A team of researchers from the St Vincent's Campus in Sydney have developed a novel way to control the extreme weight loss, common in late stage cancer, which often speeds death.
The findings, published in Nature Medicine, suggest it may soon be possible to prevent this condition, giving people the strength to survive treatment and improve their chances of recovery.

Une équipe de chercheurs a développé un nouveau moyen de controler la perte de poids extrême commune dans les derniers stages du cancer qui accélère souvent la mort.

La découverte, publiée dans Nature suggère qu'il pourrait être bientôt possible de prévenir cette condition donnant pat le fait même la force de survivre aux gens.

The team of researchers from the Centre for Immunology at St Vincent's Hospital and the University of New South Wales and the Garvan Institute of Medical Research have shown that most common cancers produce large amounts of a molecule known as MIC-1, which in turn targets receptors in the brain that switch off appetite. Antibodies against MIC-1, already developed by St Vincent's, make it possible to switch appetite back on.

L'équipe de recherche a montré que la plupart des cancers produisent beaucoup d'une molécule connue sous le nom de MIC-1 qui agit sur des récepteurs du cerveau qui influence l'appétit. Des anticorps contre MIC-1 déja développés rendent possible de redonner l'appétit.

Conversely, when normal and obese mice are treated with MIC-1, they eat less and lose a lot of weight, suggesting that MIC-1 may also form the basis of a treatment for severe obesity.

Quand les souris sont traités avec MIC-1, elles mangent moins et perdent beaucoup de poids suggérant que MIC-1 pourrait aussi être la base d'un traitement contre l'obésité.

Professor Sam Breit at the Centre for Immunology originally cloned the MIC-1 gene. He discovered that blood levels of MIC-1 were high in many patients with advanced cancers, and correlated this with the extreme weight loss seen in these patients.

In a collaboration with Professor Herbert Herzog, Director of the Neuroscience Research Program at Garvan they then analysed the effect of this molecule on metabolism and the brain control of appetite.

"This work has given us a better understanding of the part of the brain that regulates appetite. Our bodies send complex chemical signals to our brains, which interpret them and send back responses, in this case 'eat' or 'don't eat'. Our research indicated that MIC-1 is a previously unrecognised molecule sending a 'don't eat' signal to the brain," said Professor Herzog.

The study showed that if a human cancer making a lot of MIC-1 is grafted onto a mouse, that mouse lost weight dramatically. When the researchers injected that mouse with an antibody that 'mopped up' MIC-1, the weight loss was reversed. In effect, they rescued the mouse from the excessive influence of MIC-1.

It is hoped that in the near future, the MIC-1 findings will prevent a sizeable proportion of advanced cancer patients from literally wasting away. The team from St. Vincent's Hospital hope to develop a human antibody and run clinical trials in the next few years.

Professor Breit who, since discovering the MIC-1 gene in the 1990s, has conducted several internationally published studies relating to the gene's influence on coronary disease, miscarriage and cancer. He now believes the findings could also have a significant impact on a range of appetite-related disorders.

"Injecting mice with MIC-1 protein also made them stop eating, suggesting that it may be possible to use this to advantage for treating patients with severe obesity," he said.

"injecter les souris avec MIC-1 peut aussi les arrêter de manger, suggérant que c'est possible de l'utiliser pour les patients souffrant d'une obésité sévère."