Showing papers by "Jon M. Wigginton published in 2003"

Biology of childhood osteogenic sarcoma and potential targets for therapeutic development : Meeting summary

Abstract: Childhood osteogenic sarcoma (OS) is a rare bone cancer occurring primarily in adolescents. The North American pediatric cooperative groups have performed a series of clinical treatment trials in this disease over the past several decades, and biology studies of tumor tissue have been an important study component. A meeting was held in Bethesda, Maryland on November 29-30, 2001, sponsored by the NIH Office of Rare Diseases, the Children's Oncology Group, and the National Cancer Institute-Cancer Therapy Evaluation Program with the general objectives: (a) to review the current state of knowledge regarding OS biology; (b) to identify, prioritize, and support the development of biology studies of potential clinical relevance in OS; and (c) to discuss the available tissue resources and the appropriate methods for analysis of OS samples for the conduct of biology studies. This report summarizes the information presented and discussed by the meeting participants.

Synergistic Anti-Tumor Responses After Administration of Agonistic Antibodies to CD40 and IL-2: Coordination of Dendritic and CD8+ Cell Responses

Abstract: In cancer, the coordinate engagement of professional APC and Ag-specific cell-mediated effector cells may be vital for the induction of effective antitumor responses We speculated that the enhanced differentiation and function of dendritic cells through CD40 engagement combined with IL-2 administration to stimulate T cell expansion would act coordinately to enhance the adaptive immune response against cancer In mice bearing orthotopic metastatic renal cell carcinoma, only the combination of an agonist Ab to CD40 and IL-2, but neither agent administered alone, induced complete regression of metastatic tumor and specific immunity to subsequent rechallenge in the majority of treated mice The combination of anti-CD40 and IL-2 resulted in significant increases in dendritic cell and CD8 + T cell number in advanced tumor-bearing mice compared with either agent administered singly The antitumor effects of anti-CD40 and IL-2 were found to be dependent on CD8 + T cells, IFN-γ, IL-12 p40, and Fas ligand CD40 stimulation and IL-2 may therefore be of use to promote antitumor responses in advanced metastatic cancer

Lack of FasL-mediated killing leads to in vivo tumor promotion in mouse Lewis lung cancer

Abstract: Lewis lung carcinoma (3LL) cells were constitutively resistant to Fas-mediated apoptosis, but overexpression of Fas on 3LL cells allowed Fas-mediated apoptosis after crosslinking with agonist anti-Fas antibody (Jo2) in vitro. Surprisingly, Fas-overexpressing 3LL cells showed enhanced in vivo tumor progression, whereas no promotion of in vivo tumor growth was observed for dominant negative (DN) Fas-overexpressing 3LL transfectants in which the cytoplasmic death domain was deleted. In addition, the promotion of in vivo tumor growth by Fas-overexpression was reduced in gld (FasL-mutation) mice compared to normal mice. These data indicate that intact Fas/FasL cell signaling is required for the promotion of in vivo tumor growth by Fas overexpression in 3LL cells. In contrast to the efficient Fas-mediated killing induced in vitro by crosslinking with anti-Fas antibody, Fas-overexpressing 3LL cells were resistant in vitro to Fas-mediated apoptosis by activated T cells or transient FasL transfection. These data suggest that agonist anti-Fas antibody and natural FasL can transmit qualitatively different signals, and crosslinking of Fas with natural FasL on 3LL cells does not deliver the expected death signal. Thus, our results demonstrate that in some cases overexpression of Fas can result in a survival advantage for tumor cells in vivo.