Les cellulles souches et le cancer du sein.

June 24, 2013 — A promising new treatment for breast cancer being developed at Virginia Commonwealth University Massey Cancer Center and the VCU Institute of Molecular Medicine (VIMM) has been shown in cell culture and in animal models to selectively kill cancer stem cells at the original tumor site and in distant metastases with no toxic effects on healthy cells, including normal stem cells. Cancer stem cells are critical to a cancer's ability to recur following conventional chemotherapies and radiation therapy because they can quickly multiply and establish new tumors that are often therapy resistant.

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Un nouveau traitement prometteur contre le cancer du :sein:a été développé et a démontré qu'il peut tuer sélectivement les cellules souches dans des cultures de cellules en laboratoire et chez des animaux dans la tumeur originale mais aussi dans les métastases à distance avec aucun effet toxique sur les cellules saines, incluant les les cellules souches normales. Les cellules souches cancéreuses sont critiques pour la capacité du cancer de revenir après les chimios conventionnelles et la thérapie par radiation parce qu'elles peuvent se multiplier vite et établir de nouvelles tumeurs qui sont souvent résistantes.

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The study, published in the International Journal of Cancer, focuses on a gene originally cloned in the laboratory of primary investigator Paul B. Fisher, M.Ph., Ph.D. The gene, melanoma differentiation associated gene-7 (mda-7), also known as interleukin (IL)-24, has been shown to directly impact two forms of cell suicide known as apoptosis and toxic autophagy, regulate the development of new blood vessels and also play a role in promoting cancer cell destruction by the immune system. In the present study, the researchers used a recombinant adenovirus vector, an engineered virus with modified genetic material, known as Ad.mda-7 to deliver the mda-7/IL-24 gene with its encoded protein directly to the tumor.
"Therapy with the mda-7/IL-24 gene has been shown to be safe in a phase I clinical trial involving patients with advanced cancers, and prior studies in my laboratory and with collaborators have shown that the gene could also be effective against breast, prostate, lung, colorectal, ovarian, pancreatic and brain cancers," says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics program at VCU Massey, chairman of VCU School of Medicine's Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine. "Our study demonstrates that this therapy may someday be an effective way to eradicate both early and advanced stage breast cancer, and could even be used to reduce the risk of cancer recurrence."

L'étude publiée dans le Journal of Cancer mets le focus sur un gène appelé Mda-7 et aussi connu sous le nom de Il-24 et qui a démontré avoir un impact sur deux formes de suicides cellulaires :l'apoptose et l'autophagie toxique. il régule aussi le développement de nouveaux vaissaux sanguins en plus de jouer un rôle dans la destruction des cellules cancéreuses avec le système immunitaire. Dans la présente étude, les chercheurs utilisent un vecteur d'adénovirus recombinant , un virus ingéniré avec du matériel génétique connu comme AD.mda-7 pour délivrer le gène mda-7/IL-24 avec sa protéine encodé directement dans la tumeur.

The researchers found that infection of human breast cancer cells with the adenovirus decreased the proliferation of breast cancer stem cells without affecting normal breast stem cells. It was also shown to induce a stress response in the cells that led to apoptosis by disrupting Wnt/B-catenin signaling, a process cells rely upon to transmit signals that initiate biological functions critical to survival. In mouse models, the therapy profoundly inhibited the growth of tumors generated from breast cancer stem cells and also killed cancer cells in distant, uninjected tumors.
Since discovering the mda-7/IL-24 gene, Fisher and his team have worked to develop better ways to deliver it to cancer cells, including two cancer "terminator" viruses known as Ad.5-CTV and Ad.5/3-CTV. Cancer terminator viruses are unique because they are designed to replicate only within cancer cells while delivering immune-modulating and toxic genes such as MDA-7/IL-24. Coupled with a novel stealth delivery technique known as ultrasound-targeted microbubble destruction (UTMD), researchers can now systemically deliver viruses and therapeutic genes and proteins directly to tumors and their surrounding tissue (microenvironment) at both primary and metastatic tumor sites. UTMD uses microscopic, gas-filled bubbles that can be paired with viral therapies, therapeutic genes and proteins, and imaging agents and can then be released in a site and target-specific manner via ultrasound. Fisher and his colleagues are pioneering this approach and have already reported success in experiments utilizing UTMD technology and mda-7/IL-24 gene therapy in prostate and colorectal cancer models.
"We are hopeful that this targeted gene therapy could be safely combined with conventional chemotherapies to significantly improve outcomes for patients with breast cancer and potentially a variety of other cancers," says Fisher. "When paired with promising new delivery techniques such as UTMD, physicians may one day be able to better target site-specific cancers and also monitor the effectiveness of these types of therapies in real time."

In the present study, the researchers used a recombinant adenovirus vector, an engineered virus with modified genetic material, known as Ad.mda-7 to deliver the mda-7/IL-24 gene with its encoded protein directly to the tumor.
"Therapy with the mda-7/IL-24 gene has been shown to be safe in a phase I clinical trial involving patients with advanced cancers, and prior studies in my laboratory and with collaborators have shown that the gene could also be effective against breast, prostate, lung, colorectal, ovarian, pancreatic and brain cancers,"





says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics program at VCU Massey, chairman of VCU School of Medicine's Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine. "Our study demonstrates that this therapy may someday be an effective way to eradicate both early and advanced stage breast cancer, and could even be used to reduce the risk of cancer recurrence."
The researchers found that infection of human breast cancer cells with the adenovirus decreased the proliferation of breast cancer stem cells without affecting normal breast stem cells. It was also shown to induce a stress response in the cells that led to apoptosis by disrupting Wnt/B-catenin signaling, a process cells rely upon to transmit signals that initiate biological functions critical to survival. In mouse models, the therapy profoundly inhibited the growth of tumors generated from breast cancer stem cells and also killed cancer cells in distant, uninjected tumors.
Since discovering the mda-7/IL-24 gene, Fisher and his team have worked to develop better ways to deliver it to cancer cells, including two cancer "terminator" viruses known as Ad.5-CTV and Ad.5/3-CTV. Cancer terminator viruses are unique because they are designed to replicate only within cancer cells while delivering immune-modulating and toxic genes such as MDA-7/IL-24. Coupled with a novel stealth delivery technique known as ultrasound-targeted microbubble destruction (UTMD), researchers can now systemically deliver viruses and therapeutic genes and proteins directly to tumors and their surrounding tissue (microenvironment) at both primary and metastatic tumor sites. UTMD uses microscopic, gas-filled bubbles that can be paired with viral therapies, therapeutic genes and proteins, and imaging agents and can then be released in a site and target-specific manner via ultrasound. Fisher and his colleagues are pioneering this approach and have already reported success in experiments utilizing UTMD technology and mda-7/IL-24 gene therapy in prostate and colorectal cancer models.
"We are hopeful that this targeted gene therapy could be safely combined with conventional chemotherapies to significantly improve outcomes for patients with breast cancer and potentially a variety of other cancers," says Fisher. "When paired with promising new delivery techniques such as UTMD, physicians may one day be able to better target site-specific cancers and also monitor the effectiveness of these types of therapies in real time."

Il y a de plus en plus de preuves que le cancer du sein n'est pas une maldie unique. Les scientifiques maintenant voient le cancer du sein comme une maladie hétérétogène faite de beaucoup de variétés et sous-types de maladies. Cette conservation a conduit à penser que les tumeurs du seins viennent de différents types de cellules qui pourraient bien inclure les cellules souches ou des cellules descendantes qui ont subi des accidents génétiques.

Cette possibilité a suscité un grand intérêt pour comprendre la composition normal des cellules du sein incluant la cellule souche. Une question qui revêtait un caractère particulier d'intérêt était de savoir si la cellule souche du exprimait les récepteurs pour oestrogène ou pour progestérone et le marqueur HER2, parce que ça aurait aider à définit les types de canceret aussi aurait permit une approche thérapeuthique.

Les scientifiques ont trouvé que les cellules souches n'exprimaient pas ces caractéristiques mais exprimaient certains marqueurs basiques. Ces caractéristiques définissent ainsi le sous-type basique du cancer du sein qui est le plus commun des cancers chez les femmes qui ont le gène prédisposant BRCA1.

Ces découvertes supportent les découvertes antérieures que les cellules souches du sein, ou leurs proches descendantes, sont les cellules par lesquelles les tumeurs arrivent. Le docteur Visvader qui a conduit l'équipe de cherheurs avec le docteur Linderman à Wehi a dit : "Cette découverte faite par MArie-Liesse Asselin-Labat dans notre laboratoire renforce le besoin de comprendre la biologie normale des cellules souches du sein. Notre espoir est qu'à long terme nous identifions de nouveaux agents thérapeuthique contre le cancer du sein particulièrement celui du type basique. Les médicaments comme le Taximofen, les inhibiteurs d'aromase ou l'herceptine sont inefficace contre les tumeurs de types basique et la chimio est la seule option.

Les recherches continuent.