The p73 locus is commonly deleted in non-Hodgkin's lymphomas.

Rearrangements involving the 1p36 chromosomal region occur frequently in NHL, suggesting the existence of tumor suppressor gene(s) that are important in lymphomagenesis. p73 is closely related to the tumor suppressor p53 and maps to the chromosome 1p36 region. Here we report heterozygous deletions of the p73 locus in 25% of FL and 27% of DLBCL cases, as detected by FISH. Immunohistochemical analysis showed that four out of five cases with p73 deletions also exhibited increased Ki67 expression, indicating higher proliferation rates of the tumor cells. Our results demonstrate a high proportion of p73 locus specific deletions in NHL and suggest that deletion of this locus may play a role in the progression of NHL.

Targeted therapies for solid tumors: current status and future perspectives.

The therapeutic benefits of targeted clinical interventions with increased selectivity and fewer adverse effects hold great promise in the treatment of solid malignancies, both in monotherapy and in combination. Molecular targeted therapies offer increasingly customized solutions based on the targeting of multiple specific pathways essential for cancer development and metastasis, allowing the maintenance of quality of life while efficiently attacking the tumor. To date, several monoclonal antibodies (mAbs) and small-molecule inhibitors have been approved for the treatment of colorectal, breast, head and neck, non-small cell lung and renal cell cancer. A number of additional targeted therapies are currently being investigated in ongoing clinical trials in various tumor types such as lung, gastric, cervical, uterine melanoma, and brain tumors. This article describes current and newly developed targeted therapies in solid tumors, with a special focus on tyrosine kinase inhibitors. These include mAbs and small-molecule inhibitors that aim to specifically disrupt receptor signaling pathways, which are essential for proliferation, survival and migration of tumor cells.

Squamous cell carcinoma related oncogene/DCUN1D1 is highly conserved and activated by amplification in squamous cell carcinomas.

Chromosomal amplification at 3q is common to multiple human cancers, but has a specific predilection for squamous cell carcinomas (SCC) of mucosal origin. We identified and characterized a novel oncogene, SCC-related oncogene (SCCRO), which is amplified along the 3q26.3 region in human SCC. Amplification and overexpression of SCCRO in these tumors correlate with poor clinical outcome. The importance of SCCRO amplification in malignant transformation is established by the apoptotic response to short hairpin RNA against SCCRO, exclusively in cancer cell lines carrying SCCRO amplification. The oncogenic potential of SCCRO is underscored by its ability to transform fibroblasts (NIH-3T3 cells) in vitro and in vivo. We show that SCCRO regulates Gli1--a key regulator of the hedgehog (HH) pathway. Collectively, these data suggest that SCCRO is a novel component of the HH signaling pathway involved in the malignant transformation of squamous cell lineage.

The NF-kappaB signalling pathway: a therapeutic target in lymphoid malignancies?

Nuclear factor-kappaB/reticuloendotheliosis (NF-kappaB/Rel) designates a family of transcription factors that influence the activation of a multitude of genes critically involved in immune and inflammatory responses. Recently, genetic and biochemical evidence has accumulated, suggesting that constitutive activation of NF-kappaB/Rel proteins plays an important role in the development/progression of B and T cell lymphoid malignancies. In particular, genetic and molecular alterations of NF-kappaB family members and their transcriptional target genes have been implicated in the development of diffuse large B cell lymphoma and mucosa-associated lymphoid tissue lymphoma. Although NF-kappaB/Rel proteins represent an integrating point of several pathways, potentially contributing to several diseases, their unique activation depends on cell type and stimulus. Considering the NF-kappaB specificity in lymphoid cells, molecules that finely modulate the activity of these NF-kappaB components and dampen the inappropriate proliferation of lymphocytes may represent a novel pharmacological intervention to several lymphoid malignancies.

Actvation of NF-kappaB by the API2/MALT1 fusions inhibits p53 dependant but not FAS induced apoptosis: a directional link between NF-kappaB and p53.

Interactions between survival pathways and apoptotic cascades play a determinant role in the maintenance of neoplastic clone proliferation and impaired response to apoptosis. Recently, we established a novel interplay between the NF-kappaB survival- and p53 death-pathways in a tumor model system that represents the most common extranodal lymphoid cell neoplasia, MALT (Mucosa Associated Lymphoid Tissue) lymphoma. MALTs are genetically characterized by the t(11;18)(q21;q21) chromosomal translocation that results in API2/MALT1 fusion products. It was shown that distinct API2/MALT1 chimeric proteins function as oncogenes that bilaterally confer a proliferative advantage to the neoplastic clone by activating the NF-kappaB signaling pathway and also inhibiting p53 mediated cell death. Here, we demonstrate that API2/MALT1 mediated inhibition of apoptosis is p53 specific, as distinct API2/MALT1 fusion proteins fail to protect cells from FAS induced cell death. Furthermore, we demonstrate that API2/MALT1 mediated NF-kappaB activation does not alter p53 protein levels or subcellular localization suggesting a post-translational or indirect mechanism of p53 deregulation.

Activation of NF-kappaB and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis.

Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common extranodal lymphoid cell neoplasia; it frequently follows chronic bacteria-induced inflammation in various tissues. MALT lymphomas are characterized genetically by the t(11;18)(q21;q21) translocation, which yields chimeric transcripts encoding structurally distinct API2/MALT1 fusion proteins. In this study, we provide functional evidence for the contribution of API2/MALT1 fusion proteins to transformation of cells in culture by activating the NF-kappaB pathway through a RelB/p50 dimer. Using microchip gene expression analysis, we demonstrate that different forms of the API2/MALT1 proteins activate both unique and overlapping gene programs in cells. In addition to this genome reprogramming, expression of distinct API2/MALT1 fusion products inhibits DNA damage-induced, p53-mediated apoptosis in an NF-kappaB-dependent manner. Collectively, these data reveal previously unknown functional diversity among API2/MALT1 fusion products and their function in NF-kappaB signaling as it connects to the apoptotic program, a pathway with strong relevance to cancer. Furthermore, they provide evidence underlying the emerging role of the NF-kappaB signaling pathway in the inhibition of apoptosis.

CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals.

Recently a Drosophila p53 protein has been identified that mediates apoptosis via a novel pathway involving the activation of the Reaper gene and subsequent inhibition of the inhibitors of apoptosis (IAPs). The present study found that CIAP1, a major mammalian homolog of Drosophila IAPs, is irreversibly inhibited (cleaved) during p53-dependent apoptosis and this cleavage is mediated by a serine protease. Serine protease inhibitors that block CIAP1 cleavage inhibit p53-dependent apoptosis. Furthermore, activation of the p53 protein increases the transcription of the HTRA2 gene, which encodes a serine protease that interacts with CIAP1 and potentiates apoptosis. These results demonstrate that the mammalian p53 protein may activate apoptosis through a novel pathway functionally similar to that in Drosophila, which involves HTRA2 and subsequent inhibition of CIAP1 by cleavage.

p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas.

Interactions between the p53 and PI3K/AKT pathways play a significant role in the determination of cell death/survival. In benign cells these pathways are interrelated through the transcriptional regulation of PTEN by p53, which is required for p53-mediated apoptosis. PTEN exerts its effects by decreasing the phosphorylated AKT fraction, thereby diminishing prosurvival activities. However, the link between these pathways in cancer is not known. In this study, PIK3CA, encoding the p110alpha catalytic subunit of PI3K, is identified as an oncogene involved in upper aerodigestive tract (UADT) carcinomas. Simultaneous abnormalities in both pathways are rare in primary tumors, suggesting that amplification of PIK3CA and mutation of p53 are mutually exclusive events and either event is able to promote a malignant phenotype. Moreover, the negative effect of p53 induction on cell survival involves the transcriptional inhibition of PIK3CA that is independent of PTEN activity, as PTEN is not expressed in the primary tumors. Conversely, constitutive activation of PIK3CA results in resistance to p53-related apoptosis in PTEN deficient cells. Thus, p53 regulates cell survival by inhibiting the PI3K/AKT prosurvival signal independent of PTEN in epithelial tumors. This inhibition is required for p53-mediated apoptosis in malignant cells.

Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas.

Amplification of the 3q26-q27 has a high prevalence in squamous cell carcinomas of mucosal origin, including those originating in the head and neck region. To elucidate its role as a prognostic tool in head and neck squamous cell carcinoma, a yeast artificial chromosome (YAC) contig spanning the entire 3q26-27 region was constructed. The minimal region of amplification was refined within a 1- to 2-Mb genomic segment contained within three overlapping, nonchimeric YAC clones using sequential fluorescent in situ hybridization analysis. These YAC clones containing the apex of amplification were used to develop a two-color fluorescence in situ hybridization assay and applied to the detection of 3q copy numbers in interphase nuclei on archival tumor tissue from 29 cases of normal mucosa, 20 of premalignant mucosa, and 50 of invasive head and neck squamous cell carcinomas. The presence of 3q amplification increased from 3% in normal mucosa to 25% in premalignant mucosa and 56% in invasive cancers (P < 0.01). In invasive tumors, low-level 3q amplification (3 to 4 X copy number) was identified in 18 of 50 primary head and neck cancers and high-level amplification (>4 X copy number) in 10 of 50 cases. With a median follow-up of 82.5 months, an increasing proportion of recurrences (32%, 72%, and 90%; P = 0.003) and cancer-related deaths (14%, 44%, and 70%; P = 0.006) were seen in patients with normal 3q copy number, low-level amplification, and high-level amplification, respectively. The 3-year disease-free (69%, 56%, and 10%; P = 0.001) and cause-specific (94%, 83%, and 40%; P = 0.01) survivals also decreased from normal copy number to low-level and high-level amplification. Only high-level amplification at 3q remained a significant prognostic variable on multivariate analysis including common prognostic predictors for both disease-free (relative risk, 5.1; 95% confidence interval = 1.9 to 13.9) and cause-specific survival (relative risk, 7.6; 95% confidence interval = 1.9 to 29.6). The findings suggest that the 3q copy number status is an important marker for tumor progression and prognostication in patients with head and neck squamous cell carcinoma.