Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differences in growth and in response to antineoplastic drugs between s.c. and orthotopically implanted tumors in nude mice and between the primary tumor and the metastases in human tumors suggest that implantation site may alter the molecular regulation of tumor cells. We assessed the influence of implantation site on cell cycle and apoptotic regulation and the possible contribution of the implantation site in directing the choice of metastatic site by comparing the behavior of tumor aliquots of two human pancreatic xenografts (NP18 and NP9) implanted in the organ where the tumor grows (orthotopically), in heterotopic sites (the site of metastases (liver), and in nonmetastatic sites (subcutis and colon). We observed that implantation site changes tumor growth by altering apoptotic or cell cycle regulation in a tumor-specific manner. In the NP18 tumor it occurs by altering apoptotic induction and activation of the Bad/Bcl-XL/caspase-3 pathway through AKT and Erk regulation, but in the NP9 tumor by changing the activation and/or expression of the proteins that regulate the cell cycle (Erk, PCNA, and cyclin B1). We also observed that implantation site alters the metastatic pattern of the NP9 tumor, originating a new metastatic site.
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PMID:Heterotopic implantation alters the regulation of apoptosis and the cell cycle and generates a new metastatic site in a human pancreatic tumor xenograft model. 1208 58

The genetic mechanisms that control proliferation of childhood musculoskeletal malignancies, notably Ewing's tumor (ET) and rhabdomyosarcoma (RMS), remain largely unknown. Most human cancers appear to overexpress at least one of the G1 cyclins (cyclins D1, D2, D3, E1, and E2) to bypass normal regulation of cell cycle G1 progression. We compared the gene expression profiles of 7 ET and 13 RMS primary tumor samples and found overexpression of cyclin D1 in all 7 ET samples. In contrast, RMS samples expressed higher levels of cyclin D2, cyclin D3, and cyclin E1. This was confirmed by quantitative reverse transcription-polymerase chain reaction and Western blot. The relative roles of RAS-extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3'-kinase (PI3K)-AKT pathways in the regulation of D-type cyclin expression in these tumors were then assessed. Inhibition of either pathway reduced expression of cyclins D1, D2, and D3 in RMS lines, whereas only PI3K inhibitors blocked cyclin D1, D2, and D3 expression in ET lines. Furthermore, PI3K-AKT appeared to regulate D-type cyclin transcription in RMS lines through FKHR and FKHRL1. Finally, the role of the ET-associated EWS-FLI1 fusion gene in regulating D cyclin expression was studied. Inhibition of EWS-FLI1 expression in the TC71 ET line decreased cyclin D1 levels but increased cyclin D3 levels. In contrast, induction of EWS-FLI1 expression in the RD RMS cell line increased cyclin D1 expression but decreased cyclin D3 expression. Our results demonstrate distinct regulation of D-type cyclins in ET and RMS and indicate that EWS-FLI1 can modulate the expression of D-type cyclins independent of cellular backgrounds.
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PMID:Selective usage of D-Type cyclins by Ewing's tumors and rhabdomyosarcomas. 1534 83

Non-small cell lung cancer (NSCLC) expresses a particularly aggressive metastatic phenotype, and patients with this disease have a poor prognosis. CXC chemokine receptor 4 (CXCR4) is a cell surface receptor that has been shown to mediate the metastasis of many solid tumors including lung, breast, kidney, and prostate. In addition, overexpression of the epidermal growth factor receptor (EGFR) is associated with the majority of NSCLC and has been implicated in the process of malignant transformation by promoting cell proliferation, cell survival, and motility. Here we show for the first time that activation of the EGFR by EGF increases CXCR4 expression and the migratory capacity of NSCLC cells. Furthermore, many solid tumors are associated with low oxygen tension, and when NSCLC cells were cultured with EGF under hypoxic conditions, CXCR4 expression was dramatically enhanced. A molecular analysis of these events indicated that augmented CXCR4 expression was regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signal transduction pathway, activation of hypoxia inducible factor (HIF) 1alpha, and ultimately HIF-1-dependent transcription of the CXCR4 gene. Thus, a combination of low oxygen tension and overexpression of EGFR within the primary tumor of NSCLC may provide the microenvironmental signals necessary to upregulate CXCR4 expression and promote metastasis.
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PMID:Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. 1580 68

New therapeutic agents are needed for the treatment of androgen-independent prostate cancer (PrCa). We have investigated the effect of methylseleninic acid (MSA) on tumor stage-specific prostate cells derived from the C3 (1)/Tag model for PrCa: Pr111, a slow-growing and nontumorigenic cell line isolated from a prostate intraepithelial neoplasia lesion; Pr14, a tumorigenic line derived from a primary tumor; and Pr14C1, a sub-clone of Pr14 explanted from a lung metastasis. We demonstrate that MSA strongly inhibits cell growth and induces apoptosis in C3 (1)/Tag tumor cells, in a dose-dependent manner. A decrease in phosphorylated ERK1/2 and AKT was also found in tumor cells, but not in Pr111. Microarray analysis using affymetrix showed that the number of genes with an altered expression in tumor cells is significantly higher (p < 0.01) than in nontumoral cells. Pathways analyses revealed a decrease in the expression of genes involved in metabolism (Fabp5, Cyba), signal transduction (ERK, AKT), angiogenesis (neuropilin-1, Flt-4) and transcription (cAMP response element-binding protein) in tumor cells. The expression of neuropilin-1, a protein involved in VEGF signaling and tumor angiogenesis, was 97-fold repressed in Pr14 cells treated with MSA. Combination treatments using low doses of etoposide or taxotere (docetaxel), plus low doses of MSA revealed a strong enhancement of cell growth inhibition and apoptosis in tumor cells. Our in vivo studies using Pr14 cells xenografted into nude mice demonstrated that MSA significantly enhances the chemotherapeutical effect of etoposide, resulting in 78.3% tumor growth inhibition. These results suggest that MSA could be used against PrCa to enhance the effect of etoposide.
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PMID:Methylseleninic acid enhances the effect of etoposide to inhibit prostate cancer growth in vivo. 1752 Jun 73

Liver is the most common organ of colorectal cancer (CRC) metastasis, and hepatic metastasis (HM) is regulated by complex protein network. Hence, we initiated a proteomic survey to seek interrelated multiplex markers related with HM. A total of 34 unique differential proteins were identified in the primary tumor tissues from 14 CRC patients with/without HM. A differential protein cluster, consisting of 17 proteins throughout PI3K/AKT pathway, was deduced and validated by Western blot. A three-protein signature elicited from the protein cluster, phosphorylated IkappaBalpha, TNFalpha and MFAP3L, was detected by immunohistochemistry on 105 pairs of CRC and normal samples. The positive protein signature was specifically correlated with HM (P < 0.001), and classified the HM risk of CRC patients with high sensitivity (92.85 +/- 4.87%) and specificity (94.94 +/- 2.5%). The high-risk group had significantly decreased overall survival (P < 0.001). Furthermore, RKO and HT29, two colon cancer cells with different expression status of the protein signature, were used to construct the nude mouse model of HM. And the HM occurrence of RKO cell (4/5) was dramatically higher than that of HT29 cell (1/5). Therefore, the protein signature derived from PI3K/AKT pathway is likely a promising multiplex biomarker for HM of CRC.
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PMID:Evaluation of hepatic-metastasis risk of colorectal cancer upon the protein signature of PI3K/AKT pathway. 1857 Apr 57

Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both cell lines and primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr(705)) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, and D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data show that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib.
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PMID:Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas. 1900 35

We have investigated the role of the signaling intermediate, EPS8, in tumor progression using a model system and in vivo. HN4 primary tumor cells express low levels of EPS8, similar to normal keratinocytes, and show minimal invasion in vitro in response to epidermal growth factor, whereas HN12 cells express high levels of EPS8 and are highly motile in vitro and tumorigenic in vivo. Additional independent tumor cell lines also showed elevated EPS8 expression compared with normal keratinocytes. Using retroviral transduction, we generated HN4 cell lines expressing EPS8 (HN4/EPS8) at levels equivalent to those present in HN12 cells. HN4/EPS8 cells showed increased proliferation and migration compared with controls, together with elevated expression and activity of matrix metalloprotease (MMP)-9, which was dependent on protein kinase B (AKT) activity. Introduction of plasmids that direct synthesis of EPS8 short hairpin RNA (shRNA) into HN12 cells resulted in decreased EPS8 expression in these cells, which correlated with a decrease in their capacity to migrate and invade in vitro. In addition, shRNA-mediated knockdown of EPS8 reduced expression and activity of MMP-9 produced by these cells and reduced MMP-9 promoter activity. EPS8 knockdown cells showed decreased tumorigenicity in vivo compared with controls and lower MMP-9 expression. Conversely, overexpression of EPS8 in HN4 cells was sufficient to induce growth of these non-tumorigenic cells in orthotopic transplantation assays. Furthermore, EPS8 expression in clinical samples of squamous cell carcinoma showed variable expression levels and broadly paralleled expression of MMP-9. The data support a role for EPS8 in squamous carcinogenesis.
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PMID:Role for EPS8 in squamous carcinogenesis. 1900 10

Metastasis may arise years after removal of a primary tumor. The mechanisms allowing latent disseminated cancer cells to survive are unknown. We report that a gene expression signature of Src activation is associated with late-onset bone metastasis in breast cancer. This link is independent of hormone receptor status or breast cancer subtype. In breast cancer cells, Src is dispensable for homing to the bones or lungs but is critical for the survival and outgrowth of these cells in the bone marrow. Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TNF-related apoptosis-inducing ligand (TRAIL), factors that are distinctively expressed in the bone metastasis microenvironment. Breast cancer cells that lodge in the bone marrow succumb in this environment when deprived of Src activity.
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PMID:Latent bone metastasis in breast cancer tied to Src-dependent survival signals. 1957 4

Oral squamous cell carcinoma is the sixth most common cancer in the world and the seventh most common cancer in Vietnam. The RAS and PI3K-AKT signaling pathways play an important role in oral carcinogenesis. Our previous study on PI3K signaling pathway showed the absence of PIK3CA and PTEN gene mutations in Vietnamese oral cancer. We thus hypothesized that the RAS could be more likely activated as an upstream effector. However, the status of RAS mutations in Vietnamese oral cancer had not been studied. In the present study, Fifty six primary tumor DNA samples were screened for mutations of hot spots in exons 1 and 2 of H-RAS and a part of the samples for exon 7 of ERK2 gene in which we previously reported a mutation in an OSCC cell line. The H-RAS mutations were detected in 10 of 56 tumors (18%). Two novel mutations were found, one was an insertion of three nucleotides (GGC) between codons 10 and 11 resulting in in-frame insertion of glycine (10(Gly)11) and the other was a missense mutation in codon 62 (GAG>GGG). We also found T81C single nucleotide polymorphism in 12 of 56 tumors (22%) and there was no mutation in exon 7 of ERK2 gene. The H-RAS mutation incidence showed significant association with advanced stages of the tumor and also with well-differentiated tumor grade. Our study is the first to report H-RAS mutation from Vietnamese ethnicity, with two novel mutations and relatively high incidence of H-RAS mutations. The results suggest that RAS is an important member in the PI3K-AKT signaling and could play an important role in the tumorigenesis of oral carcinoma.
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PMID:Detection of two novel mutations and relatively high incidence of H-RAS mutations in Vietnamese oral cancer. 1962 22

Chronic lymphocytic leukemia (CLL) cells are susceptible to oxidative stress. The expanded porphyrin, motexafin gadolinium (MGd), reacts with intracellular reducing metabolites and protein thiols to generate reactive oxygen species (ROS). A phase II trial administered MGd 5 mg/kg/day IV for 5 days every 3 weeks until disease progression to patients with previously treated CLL and small lymphocytic lymphoma. Thirteen patients (median age 66 years) with a median of four prior therapies (range 2-9) were enrolled. Modest anti-tumor activity was seen in three patients, with improvement in lymphocytosis, lymphadenopathy and/or splenomegaly, but no patient achieved a partial or complete response by NCI 96 criteria. Flow cytometry confirmed tumor uptake of MGd. Serial increase in AKT phosphorylation in patient samples following MGd treatment was not observed, suggesting intracellular generation of ROS was not optimal. Therefore, this schedule of administration achieved MGd uptake into primary tumor cells in vivo, but clinical activity was modest.
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PMID:Effects of motexafin gadolinium in a phase II trial in refractory chronic lymphocytic leukemia. 1986 Jun 24


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