mda-7/IL-24, novel anticancer cytokine: Focus on bystander antitumor, radiosensitization and antiangiogenic properties and overview of the phase I clinical experience (Review)

Subtraction hybridization applied to a ‘differentiation therapy’ model of cancer employing human melanoma cells resulted in the cloning of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Initial studies confirm an inverse correlation between mda-7 expression and melanoma development and progression. Forced expression of mda-7 by means of a plasmid or via a replication incompetent adenovirus (Ad.mda-7) promotes growth suppression and induces apoptosis in a broad array of human cancers. In contrast, mda-7 does not induce growth suppressive or toxic effects in normal cells. Based on structure (containing an IL-10 signature motif), secretion by cells (including subsets of T-cells) and location on chromosome 1q (in an area containing IL-10- family genes), mda-7 has now been renamed mda-7/IL-24. Studies by several laboratories have uncovered many of mda-7/ IL-24\u27s unique properties, including cancer-specific apoptosisinduction, cell cycle regulation, an ability to inhibit angiogenesis, potent ‘bystander antitumor activity’ and a capacity to enhance the sensitivity of tumor cells to radiation, chemo- therapy and monoclonal antibody therapy. Moreover, based on its profound cancer tropism, substantiated by in vivo human xenograft studies in nude mice, mda-7/IL-24 (administered as Ad.mda-7) was evaluated in a phase I clinical trial in patients with melanomas and solid cancers. These studies document that mda-7/IL-24 is well tolerated and demonstrates evidence of significant clinical activity. In these contexts, mda-7/IL-24 represents a unique cytokine gene with potential for therapy of human cancers. The present review focuses on three unique properties of mda-7/IL-24, namely its potent ‘bystander antitumor activity’, ability to sensitize tumor cells to radiation, and its antiangiogenesis properties. Additionally, an overview of the phase I clinical trial is provided. These studies affirm that mda-7/IL-24 has promise for the management of diverse cancers

Identification et caractérisation d'un nouveau marqueur de surface de 55kDa. impliqué dans la progression tumorale du mélanome humain

Dans le but d'identifier de nouveaux marqueurs de surface prédictifs du phénotype invasif des cellules humaines de mélanome, une stratégie d'immunisation soustractive a été appliquée à deux types cellulaires de mélanome de phénotypes métastatiques différents. Dans cette étude, un nouvel anticoprs monoclonal LY1 a été sélectionné pour sa réactivité unique aux cellules de mélanome hautement métastatiques. Les études biochimiques menées avec LY1 MoAb montrent la réactivité de cet anticorps pour une protéine de surface de 55 kDA., localisée dans les points de contact intercellulaire et fonctionnellement impliquée dans les interactions homotypiques cellule-cellule, selon un mode d'interaction différent de celui des cadhérines et des tétraspanines. Les études fonctionnelles menées avec LY1 MoAb ont permis d'établir le rôle biologique de p55 dans la prolifération tumorale in vivo, l'invasion tumorale in vitro et dans l'étape d'intravasation tumorale et dans l'implantation métastatique spécifique d'organe dans le modèle d'étude de la formation des métastases spontanées in vivo. Une analyse immunohistochimique menée sur 59 lésions humaines de mélanomes à différents stades de la progression tumorale révèle la prsésence exclusive de p55 dans les phases les plus agressives du processus malin : ménlanomes en phase de croissance verticale et métastases. La structure moléculaire de p55 a été abordée en appliquant à la forme soluble de p55 une approche protéomique combinant l'électrophorèse 2D et la spectrométrie de masse MALDI-TOFF. Les spectres de masse peptidique obtenus après digestion trypsique ne présentent aucune homologie significative avec les protéines contenues dans les banques de données protéiques Swiss-Prot en TrEMBL. L'ensemble de ce travail a permis l'identification et la csaractérisation biochimique et fonctionnelle d'un nouvel antigène de surface de 55kDa. qui pourrait représenter un nouveau marqueur de progression tumorale du mélanome humain, non identifié à ce jourLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Blocking a novel 55 kDa melanoma-associated cell surface antigen inhibits the development of spontaneous metastases and interactions with frozen lung section

International audienceWe recently identified a novel 55-kDa cell-cell adhesion protein (p55) whose expression is upregulated in primary melanomas in the transition from radial growth phase to vertical growth phase. However, the functional role of p55 in various steps of the metastatic process had not been investigated. We provide evidence that subcutaneous injection of metastatic melanoma variant T1P26 in immunosuppressed newborn rats rapidly caused spontaneous metastatic lung lesions that could be readily detected by histochemical analysis with the anti-p55 monoclonal antibody (MAb) LY1. Subsequently, we were able to demonstrate that multiple subcutaneous injections of the LY1 MAb starting on the same day after tumor cell inoculation of T1P26 cells specifically blocked the formation of spontaneous lung metastases, yet had no effects on primary tumor growth, suggesting a critical role of p55 in the earlier steps of the intravasation process. To study later stages in spontaneous metastasis, we investigated the role of p55 in organ-specific cell adhesion of tumor cells in vitro. We showed that the T1P26 variant attached preferentially to lung frozen sections compared with other organs, reflecting the pattern of organ involvement of metastasis in vivo and that LY1 significantly blocked this interaction. However, no significant differences in attachment to lung sections were observed between the parental melanoma cell line M(4)Beu and its derived variant, although cellular topography analysis indicated a preferential attachment of a T1P26 variant on specific compartments of the lungs such as the perialveolar components, the endothelium and the vessel lumen of pulmonary venules. Attachment of the T1P26 variant to lung sections is not due to alterations of tumor cell adherence to basement membrane matrix by the LY1 MAb, suggesting that p55 is involved in cellular adhesion with cellular elements of the lung. p55 could represent a new functional constituent that contributes to the metastatic spread of melanoma cells by promoting the intravasation process and subsequent specific interactions between tumor cells and the target lung organ

Alpha cyano-4-hydroxy-3-methoxycinnamic acid inhibits proliferation and induces apoptosis in human breast cancer cells.

This study investigated the underlying mechanism of 4-hydroxy-3-methoxycinnamic acid (ACCA), on the growth of breast cancer cells and normal immortal epithelial cells, and compared their cytotoxic effects responses. Treatment of breast cancer cells (MCF-7, T47D, and MDA-231) with ACCA resulted in dose- and time-dependent decrease of cell proliferation, viability in colony formation assay, and programmed cell death (apoptosis) with minimal effects on non-tumoral cells. The ability of ACCA to suppress growth in cancer cells not expressing or containing defects in p53 gene indicates a lack of involvement of this critical tumor suppressor element in mediating ACCA-induced growth inhibition. Induction of apoptosis correlated with an increase in Bax protein, an established inducer of programmed cell death, and the ratio of Bax to Bcl-2, an established inhibitor of apoptosis. We also documented the ability of ACCA to inhibit the migration and invasion of MDA-231 cells with ACCA in vitro. Additionally, tumor growth of MDA-231 breast cancer cells in vivo was dramatically affected with ACCA. On the basis of its selective anticancer inhibitory activity on tumor cells, ACCA may represent a promising therapeutic drug that should be further evaluated as a chemotherapeutic agent for human breast cancer

Resistance of tumor cells to cytolytic T lymphocytes involves Rho-GTPases and focal adhesion kinase activation.

International audienceTumor cells evade adaptive immunity by a variety of mechanisms, including selection of variants that are resistant to specific cytotoxic T lymphocyte (CTL) pressure. Recently, we have reported that the reorganization of the actin cytoskeleton can be used by tumor cells as a strategy to promote their resistance to CTL-mediated lysis. In this study, we further examined the functional features of a CTL-resistant tumor variant and investigated the relationship between cytoskeleton alteration, the acquisition of tumor resistance to CTL-induced cell death, Rho-GTPases, and focal adhesion kinase (FAK) pathways. Our data indicate that although the resistant cells do not display an increased migratory potential, an alteration of adhesion to the extracellular matrix was observed. When Rho-GTPases were activated in cells by the bacterial CNF1 (cytotoxic necrotizing factor 1), striking changes in the cell morphology, including actin cytoskeleton, focal adhesions, and membrane extensions, were observed. More importantly, such activation also resulted in a significant attenuation of resistance to CTL-induced cell death. Furthermore, we demonstrate that FAK signaling pathways were constitutively defective in the resistant cells. Silencing of FAK in the sensitive target cells resulted in the inhibition of immune synapse formation with specific CTLs and their subsequent lysis. Expression of the FAK mutant (Y397F) resulted in an inhibition of IGR-Heu cell adhesion and of their susceptibility to specific lysis. These results suggest that FAK activation plays a role in the control of tumor cell susceptibility to CTL-mediated lysis