Our observations confirm that loss of DNA sequences on 9p, particularly the IFN genes, occurs at a significant frequency in gliomas, and may represent an important step in the progression of these tumors.
Multipoint linkage analysis was performed between the familial melanoma susceptibility locus (MLM) and two short tandem repeat markers, D9S126 and the interferon-alpha (IFNA) gene, which reside in the region of somatic loss in melanoma tumors.
The data presented here indicate that allelic loss from 9p21-p22 is a common occurrence in MM and further delineate the location of a putative 9p tumor suppressor gene(s) to a region between IFNA/IFNW and D9S171.
Although initial studies implicated that the IFN genes could serve as tumor suppressor genes, there is now data, mainly based on estimations of minimum region of overlap for the deletions, indicating that the relevant tumor suppressor gene is located centromeric of the alpha-, beta-, omega-IFN gene cluster.
The local production of high concentrations of IL-2 and IFN-a at the tumor site may directly alter tumor properties associated with invasive and metastatic phenotypes of RCC.
Both murine and human tumor cell lines that expressed gamma-IFN exhibited increased surface expression of HLA class I antigens when tested by Western blot and FACS analysis. gamma-IFN--transduced human melanoma cells were more active in stimulating tumor-specific cytolytic activity of CTLs from melanoma patients in vitro. m gamma-IFN--transduced tumor cells were substantially less tumorigenic than the corresponding parent tumor cell lines in immune-competent mice.
Using this probe, FISH analysis of primary glioblastoma tumors revealed homozygous deletions of the CDKN2 region in 6 of 9 tumors (67%) whereas a yeast artificial chromosome probe containing the interferon type I (IFN) gene cluster was deleted in only 4 cases (44%).
However, these data suggest that another tumor suppressor gene on 9p (near the IFNA locus) may contribute to the progression of differentiated adenocarcinoma of the stomach.
These results indicate that the human IFN-con1 gene in a viral vector can be used successfully in the treatment of tumors both directly and by tumor-targeted gene therapy.
We analyzed 19 samples of various astrocytic tumors (3 astrocytomas, 5 anaplastic astrocytomas, and 11 glioblastomas) for loss of heterozygosity (LOH) on chromosome 9p at 6 microsatellite loci (D9S54, IFNA, D9S171, D9S104, D9S165, and D9S166).
Previously these authors and others demonstrated frequent homozygous deletions of the chromosome 9p-localized class I interferon (IFN) gene cluster in glioblastoma tumors and cell lines.
Animals vaccinated with gamma-IFN-secreting D122 cells produced by AAV-based plasmids delivery demonstrated a significant delay in footpad tumor growth when compared with controls and DIF2 cells.
Experimental data derived from mouse B16 malignant melanoma models indicates that the weight of tumor in mice treated with IFN fusion proteins was significantly smaller than that of mice treated with interferon-gamma alone.
Consistent with STAT's limiting cell responsiveness to IFN, we found that 5-Aza-CdR treatment sensitized HT29 cells to growth inhibition by exogenous IFN-alpha2a, indicating that 5-Aza-CdR should be investigated as a potentiator of IFN responsiveness in certain IFN-resistant tumors.
Our results suggest that tumor vaccines with a potent immunoprotective effect do not necessarily have therapeutic potential and that weakly immunogenic tumors may be rendered highly immunogenic by cotransfection with the genes for B7.1 and gamma-IFN.
Nude mice bearing s.c. A431 epidermoid carcinoma and injected i.m. with 100 microg of IFN-omega pDNA, twice per week for 3 weeks, had a significant reduction in tumor volume (P = 0.009).
Comparison of these results with those obtained in a previous paper using flanking markers (D9S171, D9S942, D9S958 and IFNA) allowed us to detect two new cases of microsatellite instability (L-446 and L-442), and to confirm the occurrence of LOH at the INK4a/ARF locus in one tumor (M-3770).
To improve their effectiveness, it has been proposed that differentiation inducers, such as sodium butyrate (NaB), be used to increase the IFN sensitivity of tumors.
Cisplatin administration to nude mice bearing 3-day-old IFN-producing 8863 tumors resulted in complete tumor regression, while only a partial tumor inhibition was observed upon cisplatin treatment of mice bearing parental or control-transduced 8863 tumors.
To search for genetic changes in SP, a microdissection-based genetic analysis using polymorphic markers at 9q22 (PTCH; D9S15, D9S303, D9S287, D9S252) as well as markers at 9p21 flanking the tumor suppressor gene p16 (IFNA, D9S171) was performed.
We demonstrate here that this effect, independent of cell contact, is not inducible in the presence of tumor lysates and requires the constitutive expression of IFN stimulated gene 15 (ISG15) by malignant cells.