B7-H3

Many studies have demonstrated a relationship between soluble B7-H3 (sB7-H3) and the poor prognosis of patients with malignant tumors, and increasing evidence has shown a connection between sB7-H3 and NF-κB in tumor progression. In the present study, we demonstrate for the first time that sB7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-κB pathway. In this study, we observed that sB7-H3 was highly expressed in mB7-H3-positive pancreatic carcinoma (PCa) cells. Exogenous sB7-H3 significantly increased NF-κB activity and promoted the migration and invasion of PCa cells. Further studies proved that sB7-H3 first up-regulated TLR4 expression, then activated NF-κB signaling and finally promoted IL-8 and VEGF expression. In contrast, the silencing of TLR4 using a stable short hairpin RNA significantly decreased the sB7-H3-induced activity of NF-κB and the expression of IL-8 and VEGF in PCa cells. In vivo animal experiments further demonstrated that TLR4-knock-down tumor cells displayed a decreased ability to metastasize compared with the control tumor cells after being induced by sB7-H3. Collectively, these results demonstrate that sB7-H3 promotes invasion and metastasis through the TLR4/NF-κB pathway in pancreatic carcinoma cells.

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De nombreuses études ont démontré une relation entre B7-H3 soluble (SB7-H3) et le mauvais pronostic des patients atteints de tumeurs malignes, et plus de preuves ont montré un lien entre SB7-H3 et NF-kB dans la progression tumorale.

Dans la présente étude, nous démontrons pour la première fois que SB7-H3 favorise l'invasion et la métastase des cellules de carcinome du par la voie TLR4 / NF-kB. Dans cette étude, nous avons observé que SB7-H3 a été fortement exprimé dans les cellules (CaP) mb7-H3-positives du carcinome du pancréas.

L'exogène SB7-H3 a augmenté de manière significative l'activité de NF-kB et a favorisé la migration et l'invasion des cellules PCa. D'autres études ont montré que SB7-H3 régule à la hausse l'expression de TLR4, puis active la signalisation NF-kB et enfin promeut IL-8 et l'expression de VEGF. En revanche, la mise sous silence de TLR4 en utilisant un ARN comme stabilisateur a diminué de manière significative l'activité SB7-H3 induite par NF-kB et l'expression de l'IL-8 et de VEGF dans des cellules PCA.

Des expériences animales in vivo ont démontré en outre que knock-outer les cellules tumorales en TLR4  ont montré une diminution de la capacité à métastaser par rapport aux cellules tumorales de contrôle après avoir été induit par SB7-H3. Collectivement, ces résultats démontrent que SB7-H3 favorise l'invasion et les métastases à travers la voie TLR4 / NF-kB dans des cellules de carcinome du .

The incidence and mortality rate of oral cancer continue to rise, partly due to the lack of effective early diagnosis and increasing environmental exposure to cancer-causing agents. To identify new markers for oral cancer, we used a sialylation probe to investigate the glycoproteins differentially expressed on oral cancer cells. Of the glycoproteins identified, B7 Homolog 3 (B7-H3) was significantly overexpressed in oral squamous cell carcinoma (OSCC), and its overexpression correlated with larger tumor size, advanced clinical stage, and low survival rate in OSCC patients. In addition, knockdown of B7-H3 suppressed tumor cell proliferation, and restoration of B7-H3 expression enhanced tumor growth. It was also found that the N-glycans of B7-H3 from Ca9-22 oral cancer cells contain the terminal α-galactose and are more diverse with higher fucosylation and better interaction with DC-SIGN [DC-specific intercellular adhesion molecule-3 (ICAM-3)–grabbing nonintegrin] and Langerin on immune cells than that from normal cells, suggesting that the glycans on B7-H3 may also play an important role in the disease.

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Le taux de cancer de la bouche et la mortalité qui y est reliée continue d'augmenter, en partie en raison de l'absence de diagnostic précoce efficace et en augmentant l'exposition environnementale à des agents cancérigènes. Pour identifier de nouveaux marqueurs pour le cancer de la bouche, nous avons utilisé une sonde de sialylation pour enquêter sur les glycoprotéines exprimés de manière différentielle sur les cellules de cancer de la bouche. Parmi les glycoprotéines identifiées, B7 Homolog 3 (B7-H3) a été significativement surexprimé dans le carcinome orale spinocellulaire (CCCO), et sa surexpression corrélée avec la taille de la tumeur, le stade clinique avancé, et le faible taux de survie chez les patients CCCO.

En outre, le knockdown de B7-H3 a supprimé la prolifération des cellules tumorales, et la restauration de l'expression B7-H3a accru la croissance tumorale . On a également trouvé que les N-glycanes de B7-H3 des cellules du cancer oral Ca9-22 contiennent (...), ce qui suggère que les glycanes sur B7-H3 peuvent également jouer un rôle important dans la maladie.

Mayo Clinic researchers have identified the first immune molecule that appears to play a role in prostate cancer development and in predicting cancer recurrence and progression after surgery. The report on the B7-H3 molecule by Mayo Clinic Cancer Center appears in Cancer Research.
"This discovery will allow physicians to individualize treatment and observation plans for prostate cancer patients," says Timothy Roth, M.D., a Mayo Clinic urology resident and lead author of the study. "Being able to tell a patient his specific risk after surgery, and perhaps even prior to surgery, will be a huge step forward."

Les chercheurs de la clinique Mayo ont identifié la première molécule immunitaire qui joue un rôle dans le développement du cancer de la et dans la prévision dela progression et de la récurence après la chirurgie. Le rapport sur la molécule B7-h3 par la clinique MAyo apparait dans Cancer research "Cette découverte permettra au physicien de personnaliser le traitement et les plans d'observation pour le cancer des patients" dit Timothy Roth, un urologiste résident "ëtre capable de dire au patient son risque spécifique après la chirurgie et peut-être même avant la chirugie est un grand pas en avant."

Until now there were no strongly-predictive molecules for prostate cancer. The most notable other prostate biomarkers, prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA) are useful to diagnose prostate cancer. However, PSA tends to leave prostate cancer cells and migrate throughout the body, making it a poor target for therapy.

Jusqu'à maintenant il n'y a pas de molécules fermememtn prédictives pour le cancer de la prostate. Les autres marqueurs notables sont le psa et psma. toutefois le psa tends à quitter les cellules cancéreuses de la prostate et à migrer dans le corps ce qui en fait une pauvre cible pour une thérapie.

New research

In this study, Mayo researchers demonstrate that nearly all normal, pre-malignant and cancerous prostate cells have B7-H3 on their surface. Unlike PSA, B7-H3 stays attached to the surface of prostate cancer cells and does not appear to migrate, thus making B7-H3 a particularly attractive target for therapy. The researchers believe that B7-H3 kills or paralyzes immune cells that are trying to attack the cancer.

Dans cette étude, les chercheurs de la clinique Mayo démontre que presque toutes les cellles normales , pré-cancéreuses et cancéreuses ont le B7-H3 sur leur surface. Contrairement au psa, le B7-H3 reste attaché à la surface des cellules de la prostate cancéreuses et ne s'en éloigne pas. Ceci fait de B7-H3 une cible particulièrement attrayante pour une thérapie. Les chercheurs croient que B7-H3 tue ou paralyse les cellules immunitaire qui essaient d'Attaquer le cancer.

Their findings indicate that B7-H3 may prove useful as a diagnostic, prognostic and even therapeutic tool because it is stably or increasingly displayed by tumor cells as prostate cancers develop -- even after initiation of anti-hormone therapy, which is the most common treatment for advanced prostate cancer.

Leurs découvertes indiquent que B7-h3 peut se révéler utile pour diagnostiquer, prédire et même guérir à cause de sa stabilité ou sa capacité d'être produit par les cellules cancéreuses à mesure que le cancer se développe même après l'initiation de la thérapie anti-hormone ce qui est un traitement commun pour le cancer avancé de la prostate.

The physician-research team examined tissue from 338 consecutive patients who had cancers confined to the prostate and were treated exclusively with a radical prostatectomy (surgery to remove the prostate) between 1995 and 1998. All tumors and precancerous tissues displayed B7-H3, but patients with the highest levels of B7-H3 within their prostate tumors (19.8 percent) were four times more likely to experience cancer progression compared to those with weak levels of B7-H3 within their tumors. Moderate levels of B7-H3 also correlated with a slightly higher risk of recurrence (35 percent).

L'équipe de recherche a examiné les tissus de 338 patients qui ont eu des cancers confinés à la prostate et qui furent traité exclusivement avec la prostatectomie radicale entre 1995 et 1998. toutes les tumeurs et les tissus précancéreux ont fourni du b7-h3 mais les patients avec les plus hauts taux de b7-h3 dans leurs tumeurs (19.8%) étaient 4 fois plus à risque de voir leur cancer progresser comparé à ceux avec de faibles niveaux de b7-h3 dans leurs tumeurs. des niveaux modérés de b7-h3 indiquaient une risque plus petit de récurence (35%)

"Because B7-H3 is present in all prostate cancer tumors, and marked levels predict recurrence, we are able to forecast with much greater certainty the likelihood of cancer progression, regardless of therapeutic intervention," says Eugene Kwon, M.D., a senior investigator and urologist at Mayo Clinic.

For some patients, a 'watchful waiting' clinical approach is sometimes used to manage prostate cancer prior to resorting to therapy to see if the cancer becomes increasingly aggressive. The researchers say that the evaluation of B7-H3 levels in prostate biopsies from patients may soon help to determine which patients may benefit from a watchful waiting strategy versus early aggressive treatment.

Individualized medicine emerges

Mayo Clinic's findings on biomarker identification may accelerate the development of new forms of therapy, say the researchers. Additionally, prostate cancer now joins kidney cancer as a malignancy that can be tracked and predicted based on the presence of B7-H immune molecules.

"This is the way of the future," says Dr. Kwon, "We are becoming educated about ways to flesh out the molecular signatures of each patient's cancer. Using such molecular signatures will facilitate, for the first time, a truly individualized approach to prescribing the most appropriate therapy for a given patient. We will soon be able to tailor-make therapies for each person's cancer."

B7-H3 in the future

To understand how B7-H3 affects the immune system, and whether a mutation of B7-H3 is involved in the anti-immune activity, more research is necessary. Mayo is planning clinical trials for a number of cancers in late 2008, and researchers are currently developing the necessary therapeutic antibodies to be used in these studies. Investigators expect that clinical laboratory tests for the B7-H proteins may become available at Mayo to assist with the assessment of patients with kidney cancer by late 2007 or early 2008, and then for prostate cancer patients shortly thereafter.

Unique Mayo registry key

This study was possible because of Mayo's unique patient registry for prostate cancer. The registry contains hundreds of discrete pieces of information, ranging from environmental factors to specific medical test results, for more than 15,000 prostate cancer patients, all followed prospectively since the first patient was entered into the database in 1970. The Mayo Clinic prostate cancer and kidney cancer registries represent the most detailed and complete cancer reference tools in the world. Using the latter registry, Mayo investigators were previously able to link high levels of another B7-H molecule, B7-H1, to poor kidney cancer outcomes, including significantly shortened survival times.

Without the key road maps provided by these registries, the recognition of important molecules that drive cancer would not be feasible, say the researchers. Use of these patient registries enables laboratory science to be directly linked to patient care and survival following treatment.

"To a large extent, working with these registries dramatically lessens the time, resources and effort that are required to link a candidate molecule to its role in cancer development and progression," says Dr. Kwon, who is also the co-director of the Cancer Immunology and Immunotherapy Program in Mayo Clinic Cancer Center. "Our studies are the very first to provide a clear link between immune molecules and the behaviors of various cancers."

Dr. Kwon and his fellow researchers have been charged by Mayo Clinic to investigate all cancers for immune molecules that may govern cancer behavior while doubling as new therapeutic targets -- identifying future research targets.

Background: B7-H3 and immunology research at Mayo

Mayo Clinic Cancer Center was the first to discover the B7-H family of immune molecules -- proteins that normally help regulate the immune response process. Mayo investigators showed that B7-H3 and other members of the B7-H family, such as B7-H1, can have an inhibitory function and actually protect cancers as they develop.

Mayo Clinic identified B7-H3 as a new molecule in 2001. Mayo researchers published the first research identifying an immune molecule's role in cancer, with multiple publications pertaining to the role of B7-H1 in heralding a poor prognosis for patients with kidney cancer. Although a number of hypotheses predicted that these molecules might enable cancer development, no one had shown it clinically prior to these studies.

Thus far, the investigators have spent significant time researching the B7-H family of molecules. They have reviewed tens of thousands of samples from at least 30 different cancers, including cancers of the breast, colon, pancreas, brain and ovary, as well as mesothelioma.

In addition to Drs. Roth and Kwon, other Mayo Clinic collaborators include Christine Lohse; Yuri Sheinin, M.D., Ph.D.; Xavier Frigola Baro; Maureen Mckenney; Susan Kuntz; Brant Inman, M.D.; Amy Krambeck, M.D.; R. Jeffrey Karnes, M.D.; Michael Blute, M.D.; John Cheville, M.D.; and the co-senior investigator, Thomas Sebo, M.D.

This research was supported by The Richard M. Schulze Family Foundation, The Commonwealth Foundation for Cancer Research, The Helen and Martin Kimmel Foundation, and by the National Institutes of Health and the Department of Defense.

In accordance with the Bayh-Dole Act of 1980, Mayo Clinic holds patents to B7-H1 and has licensed the patent rights to Medarex, Inc. Dr. E. Kwon is an inventor of this technology and he and Mayo Clinic have received royalties greater than $10,000, the federal threshold for significant financial interest, from this license.

In addition, Mayo Clinic has filed a patent application related to B7-H3. Drs. E. Kwon, T. Roth and Y. Sheinin and Mses. C. Lohse and S. Kuntz are inventors of this technology.