Nerve growth factor and retinoic acid interactions in the control of small cell lung cancer proliferation.
OBJECTIVE
Nerve growth factor (NGF) has antiproliferative and differentiating effects in neuroendocrine tumors. In cell lines derived from small cell lung cancer (SCLC), NGF treatment stimulates NGF receptor expression, activates NGF secretion, inhibits proliferation and abrogates invasion. Since these effects are lost upon NGF withdrawal, it is relevant to identify other differentiation factors that may co-operate with the NGF system to control SCLC growth and differentiation.


METHODS
Retinoic acid (RA), which has been shown to inhibit cell transformation and proliferation, modulates the expression of NGF receptors and the sensitivity to NGF in different cell models. In the present study, we have investigated whether NGF and RA may interact to control the proliferation of SCLC cell lines.


METHODS
SCLC cells were exposed to 50 ng/ml NGF or 1 microM all-trans RA for different times. Cell proliferation was measured by the [(3)H]thymidine incorporation test and NGF receptor expression was evaluated by immunofluorescence.


RESULTS
We found that RA increased the expression of both trkA and p75 NGF receptors in NCI-N-592 and GLC8 cell lines and prevented the loss of both NGF production and NGF receptor expression occurring when NGF treatment was discontinued. As a result, RA, which did not inhibit the proliferation of untreated cells, abolished NGF withdrawal-related increase in cell proliferation both in vitro and in vivo, thus making permanent the antiproliferative effects of NGF.


CONCLUSIONS
These data suggest that combined treatments with NGF and RA or mimicking drugs may represent a strategy to be further investigated for the treatment of SCLC.
Fiorentini
Chiara
C
Division of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Via Valsabbina 19, 25124 Brescia, Italy.
Facchetti
Marco
M
Finardi
Alessandra
A
Sigala
Sandra
S
Páez-Pereda
Marcelo
M
Sher
Emanuele
E
Spano
PierFranco
P
Missale
Cristina
C
D018288:Carcinoma, Small Cell / Q000737:chemistry / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004347:Drug Interactions; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000473:pathology*; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D014212:Tretinoin; D004247:DNA; D020932:Nerve Growth Factor