vasoactive-intestinal-peptide and Neuroectodermal-Tumors--Primitive--Peripheral

Vasoactive intestinal peptide (VIP) is a neuromodulator and growth regulator in the developing nervous system. We analyzed 10 primitive neuroectodermal tumor (PNET) cell lines, 29 central PNET (cPNET) and 17 tumors of the Ewing's sarcoma/peripheral PNET family (ESFT) using reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern hybridization. Each of the 10 cell lines and 86.2% of cPNET expressed mRNA for VIP receptor 1 (VIPR1) compared to 52.9% of ESFT. VIPR2 was expressed in 75.8% of cPNET, in 28.6% of ESFT and in all 10 cell lines. cPNET demonstrated high-affinity binding of 125I-VIP on quantitative autoradiography and in competitive binding assays. VIP inhibited tumor cell proliferation in a dose-dependent manner in 5 of 7 PNET cell lines. We conclude that VIPR1 and VIPR2 are highly expressed in cPNET and demonstrate that VIP is a growth modulator in these tumors.

Topics: Autoradiography; Blotting, Southern; Cell Division; Child; Female; Gene Expression Regulation, Neoplastic; Growth Substances; Humans; Male; Medulloblastoma; Neuroectodermal Tumors, Primitive, Peripheral; Receptors, Vasoactive Intestinal Peptide; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Neuroblastoma, a tumor of the sympathetic nervous system, is the most common solid malignancy of childhood outside the central nervous system. Vasoactive intestinal peptide (VIP) is produced by some of these tumors, and elevated serum levels correlate with tumor cell differentiation and a favorable prognosis. It has previously been demonstrated that human neuroblastoma cell lines LA-N-5 and IMR-32 will differentiate in vitro when exposed to retinoic acid. It is now shown that VIP also induces in vitro differentiation of these neuroblastoma lines. LA-N-5 or IMR-32 cells were grown in the presence of different concentrations of VIP. Cell proliferation was suppressed, as measured by cell count, incorporation of [3H]thymidine, and measurement of the proliferation index. The degree of suppression correlated with the concentration of VIP, and the effect was indistinguishable, on a molar basis, from that seen when cells were treated with retinoic acid. Similarly, the morphological changes seen in the VIP-treated cells were the same as those seen in retinoic acid-treated ones. The effects of VIP on both cell lines, like those of retinoic acid, are reversible. The human neuroepithelioma line CHP-100, is much less sensitive to either agent. Vasoactive intestinal peptide is the first substance shown to cause differentiation of neuroblastoma cells in vitro which is also known clinically to have a specific association with that tumor. It is postulated that VIP may play a key role in the well-documented maturation of these tumors in vivo and in the normal development of the sympathetic nervous system. These findings may also have therapeutic implications for the management of this frustrating childhood malignancy.

Topics: Breast Neoplasms; Cell Differentiation; Cell Division; Cell Line; Dose-Response Relationship, Drug; Female; Humans; Kinetics; Leukemia, Promyelocytic, Acute; Neuroblastoma; Neuroectodermal Tumors, Primitive, Peripheral; Tumor Cells, Cultured; Vasoactive Intestinal Peptide