病毒的致癌作用和治癌作用

 【摘要】　经历了近一个世纪的研究, 病毒与肿瘤多样而复杂的关系逐渐得到阐明。20世纪证实了有些反转录病毒和疱疹病毒可以引发动物的淋巴瘤、白血病,对于人类情况则更为复杂。近20多年来,一些肝炎病毒与肝癌、人类乳头状瘤病毒与子宫颈癌关系的确立为利用病毒疫苗防治肿瘤成功地奠定了基础。近15年来,由于减毒活疫苗的广泛安全接种,促使溶肿瘤病毒治疗肿瘤的策略研究再度兴起,为难治性肿瘤的治疗增添了新的策略。     

Epstein-Barr virus oncogenesis and the ubiquitin-proteasome system

Epstein-Barr virus (EBV), a human herpesvirus associated with lymphoid and epithelial cell tumors, encodes several proteins that exploit the ubiquitin-proteasome system to regulate latency and allow the persistence of infected cells in immunocompetent hosts. Further modifications of ubiquitin-dependent proteolysis by activated cellular oncogenes contribute to malignant transformation. A detailed understanding of these processes may lead to the development of new therapeutic strategies for EBV-associated cancers.     

Viral immunoreceptor-associated tyrosine-based activation motifs: potential players in oncogenesis

Cancer is thought to arise as a consequence of multiple insults to a cell. Mutations that lead to increased expression or activity of proto-oncogenes or decreased expression of tumor suppressors are common insults that have been identified to date. However, when considering tumor viruses, viral proteins that modify cellular gene expression, alter host immune surveillance, or affect signaling pathways are also common players. Notably, several of these tumor viruses encode proteins containing an immunoreceptor-associated tyrosine-based activation motif (ITAM), a signaling motif recently implicated in epithelial cell oncogenesis. As expression of proteins bearing this motif is normally restricted to hematopoietic cells, recent work highlighting the consequences of ITAM expression in epithelial cells suggests it may play a role in solid tumor formation.     

Role of infectious virus expression and immune response in retrovirus-induced oncogenesis

Some of the parameters involved in retrovirus-induced oncogenesis were analyzed in newborn mice injected with Moloney-murine leukemia virus (M-MuLV) as well as in adults who received the virus by the intraperitoneal (i.p.) or intrathymic (i.t.) route. The neonatally injected mice were permissive for both viral replication and virus-induced cell-surface antigen expression on thymus cells, peripheral T and B lymphocytes, and macrophages, whereas the M-MuLV was not present in the adult i.p. injected mice. Instead, in i.t. injected mice, the virus was expressed in thymus and peripheral T cells only, but was not detected in tail extracts as assessed by means of the UV-XC plaque assay. Lack of virus spread in adult-treated animals correlated with a prompt humoral and cellular immune response, whereas the highly viremic newborn inoculated mice showed negligible virus-specific antibody production and an extremely low frequency of splenic cytotoxic T lymphocyte precursors. Moreover, immune response in both groups of adult-treated mice efficiently prevented tumor induction by Moloney-murine sarcoma virus (M-MuSV), which has the same antigenic determinants as M-MuLV, its natural helper. In contrast, M-MuSV sarcomas grew progressively in newborn inoculated mice and killed the host. Finally, 80% of neonatally injected mice developed lymphomas, whereas all treated adults remained free of disease for more than 15 months. These findings imply that the immune response may, in fact, prevent retrovirus-induced oncogenesis through restriction of virus replication and/or destruction of virus-infected cells.     

Micro-RNA and oncogenesis

MicroRNA are endogenous molecules which negatively regulate the expression of a variety of genes. These tiny non coding RNA molecules--18 to 25 nucleotides in length--repress, with efficiency and specificity- translation of target mRNA into protein, according to a process akin to RNA interference. MiRNA are critical in the development of plants and mammals since they play a key role on proteins which regulate the strict spatiotemporal control of each tissue. Very recent reports published during 2005 summer show miRNA as also involved in oncogenesis. Specific miRNA elicit oncogenic and antiapoptotic properties in lymphoma models and glioblastoma, respectively. The expression profile of the two hundred miARN, so far identified, reflects the tumor tissue lineage, leading to a potential tool for diagnosis. The occurrence of miRNA in solid tumors and haematological neoplasia opens new avenues for understanding of oncogenesis and, likely, for management of cancer diseases.     

Gender-specific polygenic control of ethylnitrosourea-induced oncogenesis in the rat peripheral nervous system

The inbred BD rat strains constitute a model system for analysis of the genetic basis of susceptibility or resistance to the development of neural tumors, as they exhibit distinct strain-specific differences regarding the sensitivity to tumor induction by the alkylating carcinogen N-ethyl-N-nitrosourea (EtNU). Among the different BD strains, BDIX and BDIV rats, respectively, are either highly susceptible or entirely resistant to the development of EtNU-induced malignant schwannomas of the peripheral nervous system (PNS), predominantly of the trigeminal nerves. We have previously mapped one locus associated with susceptibility/resistance to schwannoma induction to the telomeric third of chromosome 10 (Mss1) in segregating (BDIX x BDIV) crosses. We report on the genetic mapping of 6 further loci controlling tumor incidence or survival time on chromosomes 1 (Mss2), 3 (Mss3), 6 (Mss4), 13 (Mss5) and 15 (Mss6) as well as on chromosome 10 (Mss7) close to the centromere. Interestingly, most of these loci mediate gender-specific effects of variable strength ranging from minor influences on tumor development to complete tumor resistance. The gender specificity is reflected by the fact that male (BDIX x BDIV) F2 rats exhibit a 2-fold higher incidence of EtNU-induced schwannomas than females as well as a shorter survival time. A number of human nervous system tumors too arise with a marked gender bias. Genes mediating gender-specific predisposition of developing malignant schwannomas in the rat may be relevant for the human individual risk of developing nervous system tumors.     

Colorectal oncogenesis

Recent progress in the field of molecular biology has allowed us to identify at least two different molecular mechanisms implicated in colorectal carcinogenesis (CRC): chromosomal instability (CIN) and genetic instability. Even though the two molecular mechanisms differ, their signalling pathways, implicated in malignant transformation of colonic epithelial cells, appear to be similar. The most frequent group of CRC, which represents 80% of sporadic CRC, is characterized by allelic losses on the short arm of chromosome 17 and 8 and on the long arm of chromosome 5, 18 and 22. These allelic losses are associated with mutations in TP53, APC, SMAD2 and SMAD4 genes. All of these alterations are grouped under the phenotype CIN. A genetic instability termed MSI (microsatellite instability), which results from a mismatch repair (MMR) deficiency, appears in 12-15% of CRC cases. The presence of MMR deficiency leads to the accumulation of mutations in genes controlling cell cycle and apoptosis (TGFBRII, BAX or CASPASE5). More recently, the existence of a third phenotype was suggested. The main alteration associated with this group of tumors is the hypermethylation of the promoter region of numerous genes, leading to their inactivation. An activating mutation of BRAF is frequently associated with this phenotype. As described above, CRC shows genetic heterogeneity, however the consequences in terms of signalling pathway alterations are similar. For example, the activation of Wnt signalling pathways can result from the inactivation of the APC gene in the CIN phenotype or from an activating mutation in the β-catenin gene in MSI tumors. The inactivation of TGFβ pathways is also present in both tumor types and is driven by SMAD4, and more rarely by a SMAD2 inactivating mutation in CIN tumors, or by the existence of a frame-shift mutation occurring in a polyG coding track of the TGFβ (transforming growth factor) receptor type II in MSI tumors. The RAS-MAP kinase pathway is activated by KRAS mutations in CIN tumors or by BRAF mutations in MSI tumors. The p53 pathway is inactivated by TP53 inactivation in CIN tumors or by BAX inactivating mutations in MSI tumors.     

细胞分裂与癌发生机制研究进展

基于肿瘤病理及流行病学的长期观察,结合细胞生物学新成就,发现常见肿瘤发生与细胞分裂潜能关系密切。细胞分裂是个体生长发育及组织损伤后再生修复时必不可少的生物学行为,由于细胞分裂潜能是有限的,频繁分裂将使局部细胞的分裂潜能提前耗竭,籍此发生的细胞重新选择为细胞永生化、恶性变创造了条件。     

铁代谢与肿瘤生成

铁代谢与肿瘤发生、发展、转移及血管生成密切相关.肿瘤患者体内的铁蛋白及其受体、转铁蛋及其受体普遍呈高表达,而去铁除了可抑制肿瘤的生长外,还可减轻基质金属蛋白酶相关的肿瘤细胞的转移.     

细胞分裂与癌发生机制研究进展

基于肿瘤病理及流行病学的长期观察,结合细胞生物学新成就,发现常见肿瘤发生与细胞分裂潜能关系密切。细胞分裂是个体生长发育及组织损伤后再生修复时必不可少的生物学行为,由于细胞分裂潜能是有限的,频繁分裂将使局部细胞的分裂潜能提前耗竭,籍此发生的细胞重新选择为细胞永生化、恶性变创造了条件。     

Primate retroviruses and oncogenesis

This review summarizes the current knowledge and role of human and nonhuman primate retroviruses in the pathogenesis of neoplasia.     

Polo-like kinases and oncogenesis

Polo-like kinases (Plks) play pivotal roles in the regulation of cell cycle progression. Plk1, the best characterized family member among mammalian Plks, strongly promotes the progression of cells through mitosis. Furthermore, Plk1 is found to be overexpressed in a variety of human tumors and its expression correlates with cellular proliferation and prognosis of tumor patients. Although all Plks share two conserved elements, the N-terminal Ser/Thr kinase domain and a highly homologues C-terminal region termed the polo-box motif, their functions diverge considerably. While Plk1 is inhibited by different checkpoint pathways, Plk2 and Plk3 are activated by the spindle checkpoint or the DNA damage checkpoint. Thus, Plk2 and Plk3 seem to inhibit oncogenic transformation. Deregulation of Plk1 activity contributes to genetic instability, which in turn leads to oncogenic transformation. In contrast, Plk2 and Plk3 are involved in checkpoint-mediated cell cycle arrest to ensure genetic stability, thereby inhibiting the accumulation of genetic defects. In this review, we shall discuss the roles of Plks in oncogenesis and Plk1 as a target for therapeutic intervention against cancer.     

Molecular chaperones and the stress of oncogenesis

Protein-damaging stresses induce the expression of 'heat-shock proteins', which have essential roles in protecting cells from the potentially lethal effects of stress and proteotoxicity. These stress-protective heat-shock proteins are often overexpressed in cells of various cancers and have been suggested to be contributing factors in tumorigenesis. An underlying basis of oncogenesis is the acquisition and accumulation of mutations that provide the transformed cell with the combined characteristics of deregulated cell proliferation and suppressed cell death. Heat-shock proteins with dual roles as regulators of protein conformation and stress sensors may therefore have intriguing and central roles in both cell proliferation and apoptosis. It has been established that heat-shock proteins exhibit specificity to particular classes of polypeptide substrates and client proteins in vivo, and that chaperones can stabilize mutations that affect the folded conformation. Likewise, overexpression of chaperones has also been shown to protect cells against apoptotic cell death. The involvement of chaperones, therefore, in such diverse roles might suggest novel anticancer therapeutic approaches targeting heat-shock protein function for a broad spectrum of tumor types.     

DNA viruses and oncogenesis.

This review addresses the biology and role of DNA viruses in oncogenesis.