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In the present study, we have characterized several human thyroid cancer cell lines of different histotypes for their responsiveness to contact inhibition. We found that cells derived from differentiated carcinoma (TPC-1, WRO) arrest in G1 phase at confluence, whereas cells derived from anaplastic carcinoma (ARO, FRO and FB1) continue to grow after reaching confluence. Furthermore, we provide experimental evidence that the axis, E-cadherin/-catenin/p27Kip1, represents an integral part of the regulatory mechanism that controls proliferation at a high cell density, whose disruption may play a key role in determining the clinical behaviour of thyroid cancer. This conclusion derives from the finding that: (i) the expression of p27Kip1 is enhanced at high cell density only in cells responsive to contact inhibition (TPC-1, WRO), but not in contact-inhibition resistant cells (ARO, FRO or FB1 cells); (ii) the increase in p27Kip1 also resulted in increased levels of p27Kip1 bound to cyclin ECdk2 complex, a reduction in cyclin ECdk2 activity and dephosphorylation of the retinoblastoma protein; (iii) antisense inhibition of p27Kip1 upregulation at high cell density in confluent-sensitive cells completely prevents the confluence-induced growth arrest; (iv) proper expression and/or membrane localization of E-cadherin is observed only in cells responsive to contact inhibition (TPC-1, NPA, WRO) but not in unresponsive cells (ARO, FRO or FB1); (v) disruption of E-cadherin-mediated cellcell contacts at high cell density induced by an anti-E-cadherin neutralizing antibody, inhibits the induction of p27kip1 and restores proliferation in contact-inhibited cells; (vi) re-expression of E-cadherin into cells unresponsive to contact inhibition (ARO, FB1) induces a p27kip1 expression and growth arrest. In summary, our data indicate that the altered response to contact inhibition exhibited by thyroid anaplastic cancer cells is due to the failure to upregulate p27Kip1 in response to cellcell interactions. [ABSTRACT FROM AUTHOR]

DEP-1/HPTP?, a receptor-type protein tyrosine phosphatase, is a candidate tumor suppressor gene because its expression was blocked in rat and human thyroid transformed cells, and its restoration reverted their neoplastic phenotype. In addition, loss of DEP-1/HPTP? heterozygosity has been described in mammary, lung and colon primary tumors. We now show that DEP-1/HPTP? is drastically reduced in several cell lines originating from human epithelial pancreatic carcinomas compared with normal pancreatic tissue. We also show that the infection of AsPC1 and PSN1 cells with a recombinant adenovirus carrying r-PTP? cDNA (the rat homolog of DEP-1/HPTP?) inhibits their proliferation. Flow cytometric analysis of the infected cells demonstrated that restoration of r-PTP? activity disrupts their cell cycle and leads to apoptosis. Finally, the growth of PSN1 xenograft tumors was blocked by the intratumoral injection of a recombinant adeno-associated virus carrying r-PTP?. The data suggest that restoration of DEP-1/HPTP? expression could be a useful tool for the gene therapy of human pancreatic cancers. [ABSTRACT FROM AUTHOR]

The high mobility group A (HMGA) proteins are non-histone chromosomal proteins implicated in the organization of chromatin structure and in the assembly of protein complexes on the promoters of several inducible genes. Rearrangements of HMGA1 and HMGA2 genes, consequent to chromosomal translocation, have been frequently detected in human benign tumours of mesenchymal origin including lipomas. We have demonstrated previously that 3T3-L1 adipocytic differentiation is associated with increased HMGA1 protein levels, and that the block of HMGA1 synthesis dramatically increases the growth rate of 3T3-L1 cells and suppresses adipocytic differentiation. Here we have examined the role of a truncated HMGA1 gene in adipocytic cell growth. We have found that expression of the truncated Hmga1 gene (Hmga1/T) dramatically increases 3T3-L1 cell growth without blocking adipocytic differentiation. The Hmga1/T 3T3-L1 cells had higher E2F activity than the wild-type cells, and a deregulated cell cycle. In fact, the Hmga1/T cells had a reduced G0/G1 fraction, and a greater number of cells in S-phase. However, consistent with the benign nature of tumours associated with HMGA1 rearrangements, the Hmga1/T 3T3-L1 cells did not acquire the malignant phenotype. These results suggest a critical role played by HMGA1 rearrangements in the generation of human lipomas. [ABSTRACT FROM AUTHOR]