Accession Number:

ADA591172

Title:

Environment-Mediated Drug Resistance in Neuroblastoma

Descriptive Note:

Annual rept. 30 Sep 2012-29 Sep 2013

Corporate Author:

CHILDREN'S HOSPITAL LOS ANGELES CA

Personal Author(s):

Report Date:

2013-10-01

Pagination or Media Count:

21.0

Abstract:

During the past funded period, we have completed the first aim or our research project by demonstrating that interleukin-6 protects neuroblastoma cells from drug-induced apoptosis via activation of signal transduction and activator of transcription STAT 3 and that STAT3 is necessary to promote survival by upregulating Bcl-xL and survivin. In bone marrow samples of patients with neuroblastoma, we demonstrated the presence of a reciprocal loop of STAT3 activation in tumor cells and in monocytes-macrophages and T reg cells in which we found STAT-3 to be activated. We also demonstrated that monocytes cooperate with bone marrow-derived mesenchymal cells in activating STAT-3 by being a source of the agonistic soluble IL-6 receptor. This work was published in Cancer Research in July 2013. We have also generated NB-Tag mice that spontaneously develop neuroblastoma tumors in an IL-6 knock-out background. These mice develop tumors at a normal rate but we observed STAT3 activation in tumors suggesting the presence of alternate pathways than IL-6 responsible for STAT3 activation. We are currently testing whether these tumors are equally sensitive to chemotherapy. Further collaborative work with Dr. Seeger on the cooperation between MSC and monocytes indicate that in vivo, MSC enhance monocyte survival in tumors and increase the growth of neuroblastoma cells. Thus our data so far emphasize the important contribution of MSC and monocytes in neuroblastoma progression. They indicate that although IL-6 plays a role, there are alternate cytokines activating survival pathways such as STAT3. This will be the focus of our work during the second year of funding.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE