Abstract

CD10 (common acute lymphoblastic leukemia antigen, CALLA), originally identified as a differentiation antigen on normal and malignant lymphoid progenitors and mature polymorphonuclear leukocytes, is the zinc metalloprotease neutral endopeptidase 24.11 (NEP """"""""enkephalinase""""""""). This cell surface enzyme hydrolyzes a number of naturally occurring peptides and function sin multiple organ systems to down-regulate induced responses to peptide hormones. CD10/NEP, which is expressed at high levels in the lung , hydrolyzes the bombesin-like peptides (BLP) (bombesin, gastrin releasing peptide [GRP] and neuromedin C [GRP 18-27]. These peptides, which are secreted by pulmonary neuroendocrine cells, stimulate the growth of normal bronchial epithelia and neuroendocrine cells and fibroblasts, and certain tumor types. Small cell carcinoma (SCCa) of the lung, which are derived from continued proliferation. Cigarette smoke inactivates bronchial epithelial cell surface CD10/NEP and cigarette smokers have increased levels of BLP in their bronchioveolar lavage fluid and neuroendocrine cell hyperplasia. We find that SCCa cell lines that produce and respond to BLP have reduced levels of cell surface CD10/NEP and that growth of SCCa cell lines is inhibited by CD10/NEP addition and potentiated by CD10/NEP inhibition. Therefore, CD10/NEP appears to have an important role in regulating mitogenic peptide mediated growth of normal and malignant pulmonary cells. Loss of cell surface enzymatic activity may be an early step in the development of SCCa. To further assess the role of cell surface CD10/NEP in malignant and normal growth of bronchial epithelial, neuroendocrine and mesenchymal cells, the CD10/NEP gene will be transfected into SCCa cell lines which subsequently will be evaluated for growth, colony forming efficiency and tumorigenicity. CD10/NEP levels in normal pulmonary neuroendocrine cells and SCCa of the lung will be compared. Additional mechanisms associated with reduced cell surface CD10/NEP on normal bronchial epithelial cell and fibroblast growth will be determined by inhibiting the enzyme with organic inhibitors, anti-sense oligonucleotides and stable anti-sense constructs. o correlate in vitro observations and studies in animal models with clinical findings, specimens from patients with both malignant and non-malignant lesions of the lung will be evaluated for CD10/NEP and BLP expression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055095-03
Application #
2096326
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1991-07-17
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1995-06-30
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215