Survival signals and targets for therapy in breast implant-associated ALK--anaplastic large cell lymphoma.

Abstract

PURPOSE:

Anaplastic lymphoma kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphoma (T-ALCL) in patients with textured saline and silicone breast implants is a recently recognized clinical entity for which the etiology and optimal treatment remain unknown.

EXPERIMENTAL DESIGN:

Using three newly established model cell lines from patient biopsy specimens, designated T-cell breast lymphoma (TLBR)-1 to -3, we characterized the phenotype and function of these tumors to identify mechanisms of cell survival and potential therapeutic targets.

RESULTS:

Cytogenetics revealed chromosomal atypia with partial or complete trisomy and absence of the NPM-ALK (2;5) translocation. Phenotypic characterization showed strong positivity for CD30, CD71, T-cell CD2/5/7, and antigen presentation (HLA-DR, CD80, CD86) markers, and interleukin (IL)-2 (CD25, CD122) and IL-6 receptors. Studies of these model cell lines showed strong activation of STAT3 signaling, likely related to autocrine production of IL-6 and decreased SHP-1. STAT3 inhibition, directly or by recovery of SHP-1, and cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) chemotherapy reagents, effectively kill cells of all three TLBR models in vitro and may be pursued as therapies for patients with breast implant-associated T-ALCLs.

CONCLUSIONS:

The TLBR cell lines closely resemble the primary breast implant-associated lymphomas from which they were derived and as such provide valuable preclinical models to study their unique biology.

• Authors: Melissa G Lechner, Carolina Megiel, Connor H Church, Trevor E Angell, Sarah M Russell, Rikki B Sevell, Julie K Jang, Garry S Brody, Alan L Epstein
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 17 Pg. 4549-59 (Sep 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22791880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases
• PTPN6 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 6

Topics

• Anaplastic Lymphoma Kinase
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Implantation (adverse effects)
• Female
• Humans
• Interleukin-6 (metabolism)
• Lymphoma, Large-Cell, Anaplastic (metabolism, pathology, therapy)
• Molecular Targeted Therapy
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (antagonists & inhibitors, metabolism)
• Receptor Protein-Tyrosine Kinases (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured