Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ras activating mutations result in constitutive activation of Ras signalling pathways and occur in 30% of human malignancies. K-ras encodes two splice variants, K-ras 4A and 4B, and K-ras activating mutations which jointly affect both isoforms are prevalent in lung, pancreatic and colorectal cancers. Using RT-PCR we examined their expression in normal adult human tissues and addressed whether K-ras splicing is altered in sporadic colorectal cancer by comparing normal colon with colon carcinoma cell lines, and 'matched' tumour and tumour-free colon tissues from the same patient. K-ras 4B was expressed ubiquitously and was the predominant splice variant. K-ras 4A was expressed differentially, with detection in colorectal tumours and cell lines, and normal colon, pancreas and lung--sites where tumours with K-ras activating mutations arise. Both K-ras splice variants were co-expressed by single colon carcinoma cells. The K-ras 4A/4B ratio was significantly reduced in all 6 cell lines examined, including two that lacked K-ras activating mutations, and in 4/9 primary adenocarcinomas. We conclude that K-ras activating mutations do not affect K-ras splicing per se, both isoforms may play a role in neoplastic progression, and altered splicing of either the K-ras proto-oncogene or oncogene, in favour of K-ras 4B, may modulate tumour development.
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PMID:K-ras 4A and 4B are co-expressed widely in human tissues, and their ratio is altered in sporadic colorectal cancer. 1691 39

The molecular genetic profiles that characterize pancreatic ductal neoplasia have taken shape recently with the help of immunohistochemistry and the establishment of the nomenclature describing pancreatic ductal tumorigenesis. K-ras mutations frequently occur early, changes in the expression and genetic integrity of the p16 gene appear in intermediate lesions, and the inactivation of the p53, DPC4, and BRCA2 genes occur late in the neoplastic progression. Tumor-suppressor genes inactivated in pancreatic cancer such as ALK5, TGFBR2, MKK4, and STK11/LKB1 have been identified, although their roles in tumor progression are not yet well defined. Additional discoveries in this tumor system may be on the horizon, will further refine the molecular genetic profiles for the disease, and should suggest some clinical uses for this fund of knowledge.
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PMID:Molecular genetics of ductal pancreatic neoplasia. 1703 Nov 13

The ras mutation, which is observed in 20-30% of human nonsmall cell lung cancers (NSCLCs), is one of common genetic alterations and has been proposed to be a prognostic factor in lung cancer. Oncogene ras appears to be essential for tumor progression and maintenance. Several therapeutic agents have been developed to inhibit ras, such as FTIs and antisense oligonucleotides. A new tool for blocking oncogenes in cancer cells has emerged with the discovery that RNA interference can specifically silence expression of endogenous human genes. In the current study, we used small interfering RNA (siRNA) directed against mutant K-ras to determine the anti-tumor effects of decreasing the levels of this protein in lung cancer cell lines. Adenovirus-mediated siRNA (AdH1/siK-ras(V12)) against K-ras(V12) markedly decreased K-ras(V12) gene expression and inhibited cellular proliferation of NSCLC H441 cells that express the relevant mutation (K-ras codon 12 GGT --> GTT), but produced minimal growth inhibition on NSCLC H1650 cells that lack the relevant mutation. Pretreatment with AdH1/siK-ras(V12) completely abrogated subcutaneous engraftment of H441 cells, as compared with a 100% tumor take in animals that received control vector-treated tumor cells. The in vivo effect of AdH1/siK-ras(V12) treatment was further examined by intratumoral injections after tumor induction. Pre-existing tumor growth was reduced by 45% by a single intratumoral injection. Three or five repeat injections resulted in complete tumor regression in eight of ten nude mice. Further, 23.12% of AdH1/siK-ras(V12) treated H441 cells underwent apoptosis, as compared with 6.13%, and 8.27% in untreated and control vector-treated cells, respectively. These results indicate that adenovirus-mediated siRNA can specifically and efficiently target factors whose expression is altered in malignancy and may have the potential as a therapeutic modality to treat human lung cancer.
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PMID:Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells. 1717 15

The epidermal growth factor receptor (EGFR) is implicated in cancer progression and development and, being overexpressed in a variety of human malignancies, is an attractive target for selective anticancer therapy. EGFR tyrosine kinase inhibitors (TKIs) have been demonstrated to produce dramatic and durable responses in a fraction of non-small cell lung cancer patients. During the last few years, clinical and biological predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history seemed the most critical factor, probably because of the different spectrum of molecular abnormalities associated with cigarette-smoking exposure. Among biological predictors, several studies indicate that EGFR mutations and increased EGFR gene copy number are implicated in response to TKI therapy, with conflicting results in survival. Mutations in the EGFR gene as well as in K-ras and HER2 genes seemed to impair TKI effects, leading to TKI resistance. Because most available data come from retrospective studies, there is an urgent need to validate these results in prospective trials. Several studies have been recently completed, and these data could indicate how to properly select patients who are candidates for TKI therapy.
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PMID:Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors. 1729 17

Mutations in ras and p53 are the most prevalent mutations found in human nonmelanoma skin cancers. Although some p53 mutations cause a loss of function, most result in expression of altered forms of p53, which may exhibit gain-of-function properties. Therefore, understanding the consequences of acquiring p53 gain-of-function versus loss-of-function mutations is critical for the generation of effective therapies for tumors harboring p53 mutations. Here we describe an inducible mouse model in which skin tumor formation is initiated by activation of an endogenous K-ras(G12D) allele. Using this model we compared the consequences of activating the p53 gain-of-function mutation p53(R172H) and of deleting the p53 gene. Activation of the p53(R172H) allele resulted in increased skin tumor formation, accelerated tumor progression, and induction of metastasis compared with deletion of p53. Consistent with these observations, the p53(R172H) tumors exhibited aneuploidy associated with centrosome amplification, which may underlie the mechanism by which p53(R172H) exerts its oncogenic properties. These results clearly demonstrate that p53 gain-of-function mutations confer poorer prognosis than loss of p53 during skin carcinogenesis and have important implications for the future design of therapies for tumors that exhibit p53 gain-of-function mutations.
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PMID:An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations. 1760 51

The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for development of novel options. Aerosol gene delivery may provide the alternative for safe and effective treatment for lung cancer. Therefore, current study was performed to elucidate the potential effects of C-terminal modulator protein (CTMP) via aerosol on lung tumorigenesis. Lentiviral vector-CTMP was delivered into K-ras null lung cancer mice through the nose-only inhalation system for 30 min. After 48 h, the potential effects of CTMP on Akt1-related signals and cell cycle regulation in the lungs were evaluated by western blot, immunohistochemistry and zymography. Lentivirus-based CTMP delivery inhibited the Akt1 activity through selective suppression of Akt1 phosphorylation at Ser473. Aerosol delivery of CTMP inhibited proteins important for Akt1 signals, cell cycle and tumor metastasis in lungs of K-ras null mice. Together, our results suggest that lentivirus-mediated aerosol delivery of CTMP may be compatible with noninvasive in vivo gene therapy. Our results emphasize the importance of noninvasive-targeted delivery of CTMP for lung cancer therapy in the future. While the studies are conducted in mice, it is envisioned that noninvasive targeting the specific genes responsible for cancer progression is an attractive strategy for effective anticancer therapeutics.
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PMID:Lentivirus-mediated carboxyl-terminal modulator protein gene transfection via aerosol in lungs of K-ras null mice. 1796 Jan 62

Oncogenic events play an important role in cancer-related coagulopathy (Trousseau syndrome), angiogenesis and disease progression. This can, in part, be attributed to the up-regulation of tissue factor (TF) and release of TF-containing microvesicles into the pericellular milieu and the circulation. In addition, certain types of host cells (stromal cells, inflammatory cells, activated endothelium) may also express TF. At present, the relative contribution of host- vs tumor-related TF to tumor progression is not known. Our recent studies have indicated that the role of TF in tumor formation is complex and context-dependent. Genetic or pharmacological disruption of TF expression/activity in cancer cells leads to tumor growth inhibition in immunodeficient mice. This occurred even in the case of xenotransplants of human cancer cells, in which TF overexpression is driven by potent oncogenes (K-ras or EGFR). Interestingly, the expression of TF in vivo is not uniform and appears to be influenced by many factors, including the level of oncogenic transformation, tumor microenvironment, adhesion and the coexpression of markers of cancer stem cells (CSCs). Thus, minimally transformed, but tumorigenic embryonic stem (ES) cells were able to form malignant and angiogenic outgrowths in the absence of TF. However, these tumors were growth inhibited in hosts (mice) with dramatically reduced TF expression (low-TF mice). Depletion of host TF also resulted in changes affecting vascular patterning of some, but not all types of tumors. These observations suggest that TF may play different roles growth and angiogenesis of different tumors. Moreover, both tumor cell and host cell compartments may, in some circumstances, contribute to the functional TF pool. We postulate that activation of the coagulation system and TF signaling, may deliver growth-promoting stimuli (e.g. fibrin, thrombin, platelets) to dormant cancer stem cells (CSCs). Functionally, these influences may be tantamount to formation of a provisional (TF-dependent) cancer stem cell niche. As such these changes may contribute to the involvement of CSCs in tumor growth, angiogenesis and metastasis.
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PMID:The role of tumor-and host-related tissue factor pools in oncogene-driven tumor progression. 1802 19

Antiangiogenic therapies are promising approaches to cancer control, but the details of their effects on subsequent tumor progression are not fully understood. Such therapies have the potential to eventually generate extensive amounts of tumor ischemia, and we previously demonstrated that ischemic conditions induce K-ras mutations in cells with deficient mismatch repair (MMR) mechanisms. This suggested that similar effects on oncogene mutagenesis may accompany antiangiogenic therapy. To test this, MMR-deficient colorectal cancer cells (Dks-8) were xenografted into immune-deficient mice and treated with the antiangiogenic regimen of low-dose/metronomic cyclophosphamide for 2 weeks followed by a 2-week recovery period without therapy. This treatment resulted in transient tumor growth inhibition, increased hypoxia, and decreased microvessel density, and cancer cells from treated tumors acquired activating mutations of the K-ras oncogene (K-ras(G13D)). In vitro exposure of Dks-8 cells to the active metabolite of cyclophosphamide (4-hydroxycyclophosphamide) had no effect on the K-ras status, indicating that there was no direct action of this alkylating agent on K-ras mutagenesis. In addition, cells sorted from hypoxic regions of Dks-8 tumors were enriched in K-ras(G13D) mutants. Collectively, our studies suggest that increases in tumor hypoxia induced by antiangiogenic treatment may lead to K-ras mutation and consequently tumor progression, especially in susceptible individuals.
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PMID:Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts. 1822 82

Oncogenic K-ras mutations are frequently observed in colon cancers and contribute to transformed growth. Oncogenic K-ras is detected in aberrant crypt foci (ACF), precancerous colonic lesions, demonstrating that acquisition of a K-ras mutation is an early event in colon carcinogenesis. Here, we investigate the role of oncogenic K-ras in neoplastic initiation and progression. Transgenic mice in which an oncogenic K-ras(G12D) allele is activated in the colonic epithelium by sporadic recombination (K-rasLA2 mice) develop spontaneous ACF that are morphologically indistinguishable from those induced by the colon carcinogen azoxymethane (AOM). Similar neoplastic changes involving the entire colon are induced in transgenic mice constitutively expressing K-ras(G12D) throughout the colon (LSL-K-ras(G12D)/Villin-Cre mice). However, the biochemistry and fate of K-ras-induced lesions differ depending upon their location within the colon in these mice. In the proximal colon, K-ras(G12D) induces increased expression of procarcinogenic protein kinase C beta II (PKC beta II), activation of the MEK/ERK signaling axis and increased epithelial cell proliferation. In contrast, in the distal colon, K-ras(G12D) inhibits expression of procarcinogenic PKC beta II and induces apoptosis. Treatment of K-rasLA2 mice with AOM leads to neoplastic progression of small ACF to large, dysplastic microadenomas in the proximal, but not the distal colon. Thus, oncogenic K-ras functions differently in the proximal and distal colon of mice, inducing ACF capable of neoplastic progression in the proximal colon, and ACF with little or no potential for progression in the distal colon. Our data indicate that acquisition of a K-ras mutation is an initiating neoplastic event in proximal colon cancer development in mice.
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PMID:Oncogenic K-ras promotes early carcinogenesis in the mouse proximal colon. 1827 Oct 8

The WHO 1994 classification for endometrial hyperplasias is based on the morphologic features of the lesions. This system characterizes the nuclear cytologic morphology as typical or atypical and describes the glandular architectural pattern as simple or complex. The main problem of this classification is the poor reproducibility. Although the predictive value of the atypical category is high, there are many typical hyperplasia cases with cancer progression. Modern molecular data related to endometrial tumorigenesis and precise computerized morphometric analysis have identified the lesion that may be considered as a precursor of endometrioid adenocarcinoma. By definition, this endometrial intraepithelial neoplasia (EIN) is a clonal proliferation of architecturally and cytologically altered endometrial glands which are prone to malignant transformation to endometrioid (type I) endometrial adenocarcinoma. The morphometric basis of EIN diagnosis is the D-score (DS), which is a logical combination of three morphometric features that represent the glandular complexity, glandular volume and cytological alterations. PTEN inactivation and K-ras mutation are the earliest genetic changes that can be revealed in these lesions. Hyperplasia cases that do not fit into the EIN categories are considered as benign or hormonal endometrial hyperplasia. This is the theoretical basis of a new classification system in premalignant endometrial diseases. Retrospective clinical data proved the high predictive value of the EIN scheme, so the decision on therapy can be more established. The reproducibility is excellent with application of precise definitions and PTEN immunohistochemistry. In the "Blue book" published in 2003 the WHO introduces the new morphometric- and molecular-based EIN system, and recommends it as an alternative classification method.
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PMID:[The premalignant disease of the endometrium: endometrial intraepithelial neoplasia]. 1840 95


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