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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HPVs (human papillomaviruses) infect epithelial cells and cause a variety of lesions ranging from common warts/verrucas to cervical neoplasia and cancer. Over 100 different HPV types have been identified so far, with a subset of these being classified as high risk. High-risk HPV DNA is found in almost all cervical cancers (>99.7%), with HPV16 being the most prevalent type in both low-grade disease and cervical neoplasia. Productive infection by high-risk HPV types is manifest as cervical flat warts or condyloma that shed infectious virions from their surface. Viral genomes are maintained as episomes in the basal layer, with viral gene expression being tightly controlled as the infected cells move towards the epithelial surface. The pattern of viral gene expression in low-grade cervical lesions resembles that seen in productive warts caused by other HPV types. High-grade neoplasia represents an abortive infection in which viral gene expression becomes deregulated, and the normal life cycle of the virus cannot be completed. Most cervical cancers arise within the cervical transformation zone at the squamous/columnar junction, and it has been suggested that this is a site where productive infection may be inefficiently supported. The high-risk E6 and E7 proteins drive cell proliferation through their association with PDZ domain proteins and Rb (retinoblastoma), and contribute to neoplastic progression, whereas E6-mediated p53 degradation prevents the normal repair of chance mutations in the cellular genome. Cancers usually arise in individuals who fail to resolve their infection and who retain oncogene expression for years or decades. In most individuals, immune regression eventually leads to clearance of the virus, or to its maintenance in a latent or asymptomatic state in the basal cells.
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PMID:Molecular biology of human papillomavirus infection and cervical cancer. 1659 22

Apoptosis mediated by the proapoptotic BCL-2 family members BCL-2-associated X-protein (BAX) and BCL-2 antagonist/killer (BAK) is part of the antiviral response at the cellular level to limit virus replication. Viruses, in turn, have evolved to encode antiapoptotic BCL-2 homologs (v-BCL-2s) to prevent the premature death of the infected host cell to sustain virus replication. These same v-BCL-2 proteins cooperate with loss of retinoblastoma protein and p53 tumor suppressor function, by inactivating the BAX and BAK apoptotic pathway to promote epithelial solid tumor growth and resistance to chemotherapy. Analogously to infected cells, failure of apoptosis in tumors permits the survival of abnormal, damaged cells displaying chromosome instability that may further promote tumor progression. Thus, both infected cells and tumor cells require inhibition of the apoptotic host defense mechanism, the insights from which can be exploited for therapy development.
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PMID:Mechanisms of apoptosis regulation by viral oncogenes in infection and tumorigenesis. 1667 7

Mutations in the LMNA gene, which encodes all A-type lamins, including lamin A and lamin C, cause a variety of tissue-specific degenerative diseases termed laminopathies. Little is known about the pathogenesis of these disorders. Previous studies have indicated that A-type lamins interact with the retinoblastoma protein (pRB). Here we probe the functional consequences of this association and further examine links between nuclear structure and cell cycle control. Since pRB is required for cell cycle arrest by p16(ink4a), we tested the responsiveness of multiple lamin A/C-depleted cell lines to overexpression of this CDK inhibitor and tumor suppressor. We find that the loss of A-type lamin expression results in marked destabilization of pRB. This reduction in pRB renders cells resistant to p16(ink4a)-mediated G(1) arrest. Reintroduction of lamin A, lamin C, or pRB restores p16(ink4a)-responsiveness to Lmna(-/-) cells. An array of lamin A mutants, representing a variety of pathologies as well as lamin A processing mutants, was introduced into Lmna(-/-) cells. Of these, a mutant associated with mandibuloacral dysplasia (MAD R527H), as well as two lamin A processing mutants, but not other disease-associated mutants, failed to restore p16(ink4a) responsiveness. Although our findings do not rule out links between altered pRB function and laminopathies, they fail to support such an assertion. These findings do link lamin A/C to the functional activation of a critical tumor suppressor pathway and further the possibility that somatic mutations in LMNA contribute to tumor progression.
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PMID:Stabilization of the retinoblastoma protein by A-type nuclear lamins is required for INK4A-mediated cell cycle arrest. 1680 72

The Rb protein is a tumor suppressor, which plays a pivotal role in the negative control of the cell cycle and in tumor progression. It has been shown that Rb protein (pRb) is responsible for a major G1 checkpoint, blocking S-phase entry and cell growth. The retinoblastoma family includes three members, Rb/p105, p107 and Rb2/p130, collectively referred to as 'pocket proteins'. The pRb protein represses gene transcription, required for transition from G1 to S phase, by directly binding to the transactivation domain of E2F and by binding to the promoter of these genes as a complex with E2F. pRb represses transcription also by remodeling chromatin structure through interaction with proteins such as hBRM, BRG1, HDAC1 and SUV39H1, which are involved in nucleosome remodeling, histone acetylation/deacetylation and methylation, respectively. Loss of pRb functions may induce cell cycle deregulation and so lead to a malignant phenotype. Gene inactivation of pRB through chromosomal mutations is one of the principal reasons for retinoblastoma tumor development. Functional inactivation of pRb by viral oncoprotein binding is also shown in many neoplasias such as cervical cancer, mesothelioma and AIDS-related Burkitt's lymphoma.
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PMID:RB and cell cycle progression. 1693 40

Angiogenesis, the development of new blood vessels from pre-existing vessels, represents a fundamental step in tumor progression and metastatization. The induction of vasculature is required for growth of the tumor mass, to ensure an adequate supply of oxygen and metabolites to the tumor beyond a critical size. Tumor angiogenesis is a highly regulated process that is controlled physiologically by the tumor microenvironment and genetically by alteration of several oncogenes or tumor suppressor genes. We will focus on recent demonstrations regarding the involvement of the retinoblastoma family proteins (phosphorylated retinoblastoma (pRb), p107 and pRb2/p130) at different levels of the angiogenic process. pRb and its homologs can regulate the expression of pro- and antiangiogenic factors, such as the vascular endothelial growth factor, through an E2F-dependent mechanism. Moreover, pRb is able to modulate also the transcriptional activity of several angiogenesis-related factors like HIF-1, Id2 and Oct-1. pRb2/p130 is required for both differentiation and mobilization of bone marrow-derived endothelial cell precursors and endothelial sprouting from neighboring vessels. The involvement of the pRb pathway in the angiogenesis process has also been demonstrated by different cellular models expressing viral oncoproteins, like human papilloma virus. Moreover, some natural and synthetic compounds demonstrate their antiangiogenetic activity with a mechanism of action involving pRb. Finally, the possible prognostic value of immunohistochemical evaluation of pRb and/or pRb2/p130 expression can represent a useful tool for the characterization of the angiogenic phenotype of specific tumor histotypes.
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PMID:Involvement of RB gene family in tumor angiogenesis. 1693 54

The Rho GTPases are the molecular regulators of the cell motility processes and are involved in cell cycle progression and gene transcription. We studied the expression of Rho-like GTPases molecules, particularly Rac, Tiam1 and cdc42, in retinoblastoma and correlated these with clinicopathological parameters of the tumors. Sixty-seven tumors were included which were divided in to two groups; group A: tumors with optic nerve/choroidal/orbital invasion (n=35) and group B: tumors with no invasion (n=32). Immunohistochemistry was done on paraffin sections for all the proteins and were confirmed by Western blot on fresh tumor samples. In group A tumors, Rac was positive in 10/35 (28%), cdc42 was positive in 12/35 (34%) and Tiam1 was positive in 30/35 (85%) tumors. In group 2 tumors, Rac was positive in 5/32 (15%), cdc42 was positive in 4/32 (12%) and Tiam1 was positive in 30/32 (93%) tumors. Two groups (both invasive and non-invasive tumors) showed decreased expression of Rac1 and cdc42 whereas Tiam1 was significantly expressed in invasive tumors compared to non-invasive tumors (P<0.0001). We observed a 70K cleavage product of Tiam1 along with an 110K product by blotting in RB samples. Caspase-3 was also demonstrated in RB samples, which showed Tiam1 cleavage products. This is the first study that showed the expression patterns of Rac, cdc42 and Tiam1 in retinoblastoma tumors. Thus, further studies are required to prove the involvement of caspase-3 in the cleavage of Tiam1 in vitro in RB cells and to trace out alternative pathways involved in tumor progression.
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PMID:Expressions of Rac1, Tiam1 and Cdc42 in retinoblastoma. 1702 2

The p53 family comprises the tumor suppressor p53 and the structural homologs p63 and p73. How the three family members cooperate in tumor suppression remains unclear. Here, we report different but complementary functions of the individual members for regulating retinoblastoma protein (RB) function during myogenic differentiation. Whereas p53 transactivates the retinoblastoma gene, p63 and p73 induce the cyclin-dependent kinase inhibitor p57 to maintain RB in an active, hypophosphorylated state. DeltaNp73 inhibits these functions of the p53 family in differentiation control, prevents myogenic differentiation, and enables cooperating oncogenes to transform myoblasts to tumorigenicity. DeltaNp73 is frequently overexpressed in rhabdomyosarcoma and essential for tumor progression in vivo. These findings establish differentiation control as a key tumor suppressor activity of the p53 family.
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PMID:p53 family members in myogenic differentiation and rhabdomyosarcoma development. 1704 6

Loss of both RB1 alleles is rate limiting for development of retinoblastoma (RB), but genomic copy number gain or loss may impact oncogene(s) and tumor suppressor genes, facilitating tumor progression. We used quantitative multiplex polymerase chain reaction to profile "hot spot" genomic copy number changes for gain at 1q32.1, 6p22, and MYCN, and loss at 16q22 in 87 primary RB and 7 cell lines. Loss at 16q22 (48%) negatively associated with MYCN gain (18%) (Fisher's exact P = 0.031), gain at 1q32.1 (62%) positively associated with 6p "hot spot" gain (43%) (P = 0.033), and there was a trend for positive association between 1q and MYCN gain (P = 0.095). Cell lines had a higher frequency of MYCN amplification than primary tumors (29% versus 3%; P = 0.043). Novel high-level amplification of 1q32.1 in one primary tumor, confirmed by fluorescence in situ hybridization, strongly supports the presence of oncogene(s) in this region, possibly the mitotic kinesin, KIF14. Gene-specific quantitative multiplex polymerase chain reaction of candidate oncogenes at 1q32.1 (KIF14), 6p22 (E2F3 and DEK), and tumor suppressor genes at 16q22 (CDH11) and 17q21 (NGFR) showed the most common gene gains in RB to be KIF14 in cell lines (80%) and E2F3 in primary tumors (70%). The patterns of gain/loss were qualitatively different in 25 RB compared with 12 primary hepatocellular carcinoma and 12 breast cancer cell lines. Gene specific analysis of one bone marrow metastasis of RB, prechemotherapy and postchemotherapy, showed the typical genomic changes of RB pretreatment, which normalized after chemotherapy.
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PMID:Profiling genomic copy number changes in retinoblastoma beyond loss of RB1. 1709 72

The E2F family of transcription factors plays a pivotal role in the regulation of cellular proliferation. On the basis of sequence homology and function, eight distinct members of E2F transcription factors (E2F-1 to E2F-8) have been distinguished to date. The regulation of E2F transcription factors is closely associated with the function of the retinoblastoma family of tumor suppressors (RB pathway). In the last decade various alterations of distinct components of the RB-E2F pathway were found to be associated with tumor progression. However, no data on the role of E2F family members are available in tumor biology of ovarian cancer. Here we describe an expression study of E2F transcription factors in various human ovarian cancer cell lines; its clinical relevance was examined in a training set of 77 ovarian cancer patients. Expression levels of E2F-1, E2F-2, and E2F-8 were elevated in all the ovarian cancer cell lines studied when compared with human peritoneal mesothelial cells (HPMCs). Interestingly, EGF treatment showed a time-dependent upregulation of the activating transcription factor E2F-3 and a simultaneous increase of DP-1, the heterodimeric partner of E2F-3. High expression of E2F-1, E2F-2, and E2F-8 was found to be associated with histopathologic grade 3 tumors and residual tumor over 2 cm in diameter after primary debulking surgery in ovarian cancer patients. Taken together, these data suggest that the proliferation-promoting E2F transcription factors E2F-1 and especially E2F-2 play a pivotal role in tumor biology of ovarian cancer and may be candidates for specific therapeutic targets.
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PMID:Expression of the E2F family of transcription factors and its clinical relevance in ovarian cancer. 1734 21

The childhood eye cancer retinoblastoma is initiated by the loss of both alleles of the prototypic tumor suppressor gene, RB1. However, a large number of cytogenetic and comparative genomic hybridization (CGH) studies have shown that these M1 and M2 mutational events--although necessary for initiation--are not the only genomic changes in retinoblastoma. Some of these subsequent changes, which we have termed M3 to Mn, are likely crucial for tumor progression not only in retinoblastoma but also in other cancers. Moreover, genes showing genomic change in cancer are more stable markers and, therefore, possible therapeutic targets than genes simply differentially expressed. In this review, we provide the first comprehensive summary of the genomic evidence implicating gain of 1q, 2p, 6p, and 13q, and loss of 16q in retinoblastoma oncogenesis, including karyotype, CGH, and microarray CGH data. We discuss the search for candidate oncogenes and tumor suppressor genes within these regions, including the candidates (KIF14, MDM4, MYCN, E2F3, DEK, CDH11, and others), plus associations between genomic changes and clinical parameters. We also review studies of other regions of the retinoblastoma genome, the epigenetic changes of aberrant methylation of MGMT, RASSF1A, CASP8, and MLH1, and the roles microRNAs might play in this cancer. Although many candidate genes have yet to be functionally validated in retinoblastoma, work in this field lays out a molecular cytogenetic pathway of retinoblastoma development. Candidate cancer genes carry diagnostic, prognostic, and therapeutic implications beyond retinoblastoma.
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PMID:One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. 1743 78


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