Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy.
 ...
PMID:Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. 2261 49

The effectiveness of cetuximab (Cmab) against KRAS p.G13D mutant-type tumors has been reported. In this study, we report a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in a 65-year-old female. Considering the absence of symptoms and the post-operative risk of respiratory system complications due to multiple lung metastases, particularly at the entrance to the left main bronchus, anticancer drug therapy was selected as first-line therapy. With informed consent, FOLFOX4 [folinic acid (FOL), fluorouracil (F) plus oxaliplatin (OX)] + Cmab therapy was administered as preoperative chemotherapy. A good preoperative response was obtained to the chemotherapy, with a metastatic lesion disappearing from the entrance to the left main bronchus. Subsequent resection was performed successfully with no post-operative complications. Although a histopathological examination of the resected tissue specimen revealed residual cancer cells, it also showed the marked efficacy of the chemotherapy regimen used. In this study, we describe a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in which the patient responded well to first-line therapy with FOLFOX4 + Cmab.
 ...
PMID:Good response to leucovorin and fluorouracil plus oxaliplatin and cetuximab therapy in a patient with metastatic ascending colon cancer harboring a KRAS p.G13D mutation. 2274 Aug 93

In this review, we summarize recent progress regarding the study of the main enzymes of lipid metabolism involved in colorectal cancer development, namely of a) farnesyltransferase (Ftase), a cytosolic enzyme that catalyzes the first step in the protein farnesylation; b) farnesyl diphosphate synthase (FPPS, which yields FPP, a substrate for Ftase; c) fatty acid synthase (FAS), an enzyme required for the conversion of acetyl-CoA and malonyl-CoA to palmitate; and d) lipoprotein lipase (LPL), the crucial enzyme for intravascular catabolism of triglyceride-rich lipoproteins. Alterations in the levels of these enzymes may contribute to a cell growth advantage acquired during the carcinogenic process and to the development of malignancy. We have demonstrated an elevated Ftase activity in human colorectal cancer (CRC), with differences in Ftase activity related to histological grading, tumor location and KRAS mutation status. Moreover, the first evidence of FPPS activity in human CRC was demonstrated by our study, where a higher FPPS activity and mRNA expression was present in cancer rather than in normal mucosa. We also detected a hyperactivation of FAS in colon cancer, related to tumor location, sex and, p53 mutation status. Our data reinforce the role of lipid metabolism in the regulation of cellular metabolic processes and in carcinogenesis. Moreover, our findings suggest that biological factors including sex, gene mutation status, as well as the stratification of patients with colorectal cancer into right- and left-sided subsets may be important in patient selection for targeted therapies. Our studies in vitro demonstrated that FAS might also be a molecular target for the antiproliferative activity of olive oil polyphenols in a metabolically defined subset of patients with colon cancer. Moreover, we detected that the serum levels of FAS in patients with colorectal cancer are associated with tumor stage. Recently, we found a significant reduction in the levels of FAS and another lipogenic enzyme, LPL, in adipose tissue adjacent to tumor lesions, compared to the levels of FAS detected in paired tissue distant from neoplasia in patients with colorectal cancer. The study of metabolic changes in lipogenic enzyme pathways, as well as the determination of the distribution of individual roles within each biochemical pathway provide a rationale for selecting a particular reaction step suitable for therapeutic intervention.
 ...
PMID:A significant role of lipogenic enzymes in colorectal cancer. 2275 16

There have been significant developments in colon cancer research over the last few years, enabling us to better characterize tumors individually and classifying them according to certain molecular or genetic features. Currently, we are able to use KRAS mutational status as a guide to therapy with anti-epidermal growth factor receptor antibodies. Other molecular features under research include BRAF mutation, microsatellite instability, and CpG island methylation. These three molecular features are often associated with tumors that have overlapping phenotypes and can be present simultaneously in the same tumor. However, they carry different prognostic and predictive qualities, making analysis of their interaction relatively complex. Much research thus far has examined the clinical relevance of microsatellite instability in helping determine prognosis and the predictive value of adjuvant 5-fluorouracil chemotherapy in stages II and III colon cancers. BRAF mutation appears to be a biomarker for poor prognosis. CpG island methylation is tightly associated with microsatellite instable tumors and BRAF mutation, but its clinical utility remains uncertain. Hereby, we examine preclinical and clinical data that supports the utilization of all three phenotypes in future research applied to clinical practice.
 ...
PMID:CpG Island Methylation, Microsatellite Instability, and BRAF Mutations and Their Clinical Application in the Treatment of Colon Cancer. 2279 60

KRAS, BRAF, and PI3KCA are the most frequently mutated oncogenes in human colon cancer. To explore their effects on morphogenesis, we used the colon cancer-derived cell line Caco-2. When seeded in extracellular matrix, individual cells proliferate and generate hollow, polarized cysts. The expression of oncogenic phosphatidylinositol 3-kinase (PI3KCA H1047R) in Caco-2 has no effect, but K-Ras V12 or B-Raf V600E disrupts polarity and tight junctions and promotes hyperproliferation, resulting in large, filled structures. Inhibition of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase blocks the disruption of morphology, as well as the increased levels of c-myc protein induced by K-Ras V12 and B-Raf V600E. Apical polarity is already established after the first cell division (two-cell stage) in Caco-2 three-dimensional cultures. This is disrupted by expression of K-Ras V12 or B-Raf V600E but can be rescued by ribonucleic acid interference-mediated depletion of c-myc. We conclude that ERK-mediated up-regulation of c-myc by K-Ras or B-Raf oncogenes disrupts the establishment of apical/basolateral polarity in colon epithelial cells independently of its effect on proliferation.
 ...
PMID:K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc. 2282 22

There is a growing amount of data supporting the concept that cancers originating from the proximal and distal colon are distinct clinicopathological entities. The incidence of MSI and BRAF mutation is strongly associated with right sided tumor location, whereas there are conflicting results for KRAS mutation rates. However, to date, no data exist whether and to what extent defined colonic subsites influence MSI status, KRAS and BRAF mutation rates. We selected primary colon cancer from 171 patients operated on at our institution between 2007 and 2010. BRAF, KRAS mutation rates and microsatellite instability were determined and correlated with clinicopathological features and tumor location. MSI-h cancers were significantly associated with poor histological grade but a lower rate of distant metastases. KRAS-mutated tumors were linked to lower T-stage and better differentiation. Colon carcinomas with BRAF mutation were significantly associated with distant metastatic spread and poor histological grade. Furthermore, we found that MSI-h status, KRAS and BRAF mutation rates varied remarkably among the colonic subsites irrespective of right- and left-sided origin, respectively. The results of the current study provide further evidence that a simple classification into right- and left-sided colon carcinoma does not represent the complexity of this tumor entity.
 ...
PMID:Influence of anatomical subsite on the incidence of microsatellite instability, and KRAS and BRAF mutation rates in patients with colon carcinoma. 2289 51

A 76-year-old man with renal dysfunction received FOLFIRI due to a relapse in his pelvis after surgery for sigmoid colon cancer. FOLFIRI was continued for approximately 21 months with stabilization of disease observed on CT scans, but his tumor marker levels increased and tumors showed progression. He then began treatment with cetuximab/CPT-11, but disease progression was observed. XELOX in a low-dose was then administered, but this therapy was discontinued because of progression. He could not receive the other antitumor agents, due to mutations of the KRAS gene and renal dysfunction. Therefore, FOLFIRI was restarted, because it can be continued for long periods of time. Consequently, his tumor marker levels decreased with stabilization of disease on CT scans, and he continued the therapy for 7 months while maintaining quality of life. Ultimately, this case suggested that if there was effectiveness from a previous treatment, retreatment would be successful as chemotherapy for colon cancer in the difficult situation of selecting the other effective antitumor agents.
 ...
PMID:[A case of colon cancer with chronic renal dysfunction responding to effective retreatment with FOLFIRI]. 2290 56

Genetic and epigenetic features of sessile serrated adenoma (SSA), a precursor lesion to colon cancer with microsatellite instability (MSI), were investigated. The aim of this study was to clarify whether there are location-dependent genetic and epigenetic features in SSA. Twenty-two patients with proximal SSAs and 8 with distal SSAs were recruited. Twenty-two patients with tubular adenoma (TA) and 66 with proximal colon cancer were studied for comparison. Genetic and epigenetic features were evaluated as BRAF and KRAS mutations, MSI, hMLH1 methylation and CpG island methylator phenotype (CIMP). BRAF mutation (p=0.007) and CIMP (p=0.012) were more frequently found in proximal than in distal SSAs. Furthermore, the KRAS mutation was found only in distal SSAs. In TAs, no location-related molecular features were observed. All SSAs, TAs and 42 colon cancer lesions were microsatellite stable (MSS). Twenty-four colon cancer lesions exhibited MSI and had more frequent BRAF mutations (p<0.001), hMLH1 methylation (p<0.001) and CIMP (p<0.001). BRAF mutation occurred in only 9.5% of MSS cancers (p=0.01). In MSI cancers with the BRAF mutation, a higher correlation with CIMP (p=0.032) was observed. We demonstrated the distinct genetic and epigenetic features between proximal and distal SSAs. Similar genetic and epigenetic features were shared between proximal SSAs and proximal MSI cancers harboring the BRAF mutation. By contrast, our results allow the possibility of carcinogenesis in SSAs leading to MSS cancer with the BRAF mutation.
 ...
PMID:Sessile serrated adenoma shares similar genetic and epigenetic features with microsatellite unstable colon cancer in a location-dependent manner. 2297 61

Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation, differentiation, migration and apoptosis. We evaluate genetic variation in the c-Jun-N-terminal kinases, p38, and extracellular regulated kinases 1/2 MAPK-signaling pathways and colon and rectal cancer risk using data from population-based case-control studies (colon: n = 1555 cases, 1956 controls; rectal: n = 754 cases, 959 controls). We assess 19 genes (DUSP1, DUSP2, DUSP4, DUSP6, DUSP7, MAP2K1, MAP3K1, MAP3K2, MAP3K3, MAP3K7, MAP3K9, MAP3K10, MAP3K11, MAPK1, MAPK3, MAPK8, MAPK12, MAPK14 and RAF1). MAP2K1 rs8039880 [odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38, 0.83; GG versus AA genotype] and MAP3K9 rs11625206 (OR = 1.41, 95% CI = 1.14, 1.76; recessive model) were associated with colon cancer (P (adj) value < 0.05). DUSP1 rs322351 (OR = 1.43, 95% CI = 1.09, 1.88; TT versus CC) and MAPK8 rs10857561 (OR = 1.48, 95% CI 1.08, 2.03; AA versus GG/GA) were associated with rectal cancer (P (adj) < 0.05). Aspirin/non-steroidal anti-inflammatory drug, cigarette smoking and body mass index interacted with several genes to alter cancer risk. Genetic variants had unique associations with KRAS, TP53 and CIMP+ tumors. DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival. These data suggest that genetic variation in the MAPK-signaling pathway influences colorectal cancer risk and survival after diagnosis. Associations may be modified by lifestyle factors that influence inflammation and oxidative stress.
 ...
PMID:MAP kinase genes and colon and rectal cancer. 2302 23

Activating mutations in KRAS occur in 30% to 40% of colorectal cancers. How mutant KRAS alters cancer cell behavior has been studied intensively, but non-cell autonomous effects of mutant KRAS are less understood. We recently reported that exosomes isolated from mutant KRAS-expressing colon cancer cells enhanced the invasiveness of recipient cells relative to exosomes purified from wild-type KRAS-expressing cells, leading us to hypothesize mutant KRAS might affect neighboring and distant cells by regulating exosome composition and behavior. Herein, we show the results of a comprehensive proteomic analysis of exosomes from parental DLD-1 cells that contain both wild-type and G13D mutant KRAS alleles and isogenically matched derivative cell lines, DKO-1 (mutant KRAS allele only) and DKs-8 (wild-type KRAS allele only). Mutant KRAS status dramatically affects the composition of the exosome proteome. Exosomes from mutant KRAS cells contain many tumor-promoting proteins, including KRAS, EGFR, SRC family kinases, and integrins. DKs-8 cells internalize DKO-1 exosomes, and, notably, DKO-1 exosomes transfer mutant KRAS to DKs-8 cells, leading to enhanced three-dimensional growth of these wild-type KRAS-expressing non-transformed cells. These results have important implications for non-cell autonomous effects of mutant KRAS, such as field effect and tumor progression.
 ...
PMID:Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. 2316 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>