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)

Seventy-five to 80% of breast cancers are negative for p53 gene mutations. We have investigated the possibility that altered WAF1 genes provide an alternative mode of cell cycle disruption in these tumors. DNA from a total of 85 primary breast tumors and cell lines from both the United States and Australia were examined for WAF1 and p53 mutations. With the exception of one primary tumor containing the polymorphic codon 31 (AGC-->AGA), no missense mutations in the WAF1 gene were found in 33 primary tumors or in the 19 cell lines from the United States. By contrast, 2 of 33 tumors from Australia contained tumor-specific missense mutations in the WAF1 gene, while an additional six cases contained the AGC-->AGA polymorphic 31st codon in the WAF1 gene. The p53 mutation frequency in the Australian cohort (18%) was found to be similar to that reported by us (Glebov et al., Cancer Res., 54: 3703-3709, 1994; Runnebaum et al., Proc. Natl. Acad. Sci. USA, 88: 10657-10661, 1991) in the tumors of United States patients (13%) with sporadic breast cancer. Thus, mutations in the WAF1 gene are rare in tumors with or without p53 mutations, suggesting that except in a minor population of breast cancer patients of Caucasian origin, cell cycle dysregulation by mutated p53 or WAF1 genes may not contribute to breast tumor initiation or progression.
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PMID:Altered WAF1 genes do not play a role in abnormal cell cycle regulation in breast cancers lacking p53 mutations. 981 58

Recent studies have revealed significant efficacy of the marine sponge glycolipid, alpha-galactosylceramide (alpha-GalCer), in treatment of experimental metastatic cancers, infections, and autoimmune diseases. However, the capacity of alpha-GalCer to prevent tumor development had never, to our knowledge, been evaluated in mouse models of chemical- and oncogene-dependent carcinogenesis. In this study, we demonstrate that long-term administration of soluble alpha-GalCer, spanning the time of tumor initiation, inhibits primary tumor formation in three different models: methylcholanthrene-induced sarcomas, mammary carcinomas in Her-2/neu transgenic mice, and spontaneous sarcomas in p53-/- mice. Weekly treatment of mice with alpha-GalCer maintained lymphoid tissue natural killer cell and T cell activation and elevated serum IFN-gamma and IL-4 concentrations. Consistent with the antimetastatic activity of alpha-GalCer, prevention of methylcholanthrene-induced sarcoma was IFN-gammaand tumor necrosis factor-related apoptosis-inducing ligand dependent, but not perforin-dependent. Taken together, our results demonstrate that NK1.1+alphabetaTCR+ cell-based immune therapy can inhibit primary tumorigenesis.
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PMID:Alpha-galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. 1286 93

Genomic instability is characteristic of malignant cells, and a strong correlation exists between abnormal karyotype and tumorigenicity. Increased expression of the homologous recombination and DNA repair protein Rad51 has been reported in immortalized cell lines and multiple primary tumor cell types which could alter recombination pathways to contribute to the chromosomal rearrangements found in these cells. In addition, Rad51 participates in a complex network of interactions that includes DNA damage sensors, tumor suppressors, and cell cycle and apoptotic regulators, and mutation of many of these proteins have also been associated with tumor initiation or progression. Insights into the connection between disregulated Rad51 and malignant phenotype indicate that Rad51 is a potential target for new anti-cancer regimens including those that use siRNA technology.
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PMID:RAD51, genomic stability, and tumorigenesis. 1567 Aug 90

Mutational activation of the K-Ras proto-oncogene is frequently observed during the very early stages of colorectal cancer (CRC) development. The mutant alleles are preserved during the progression from pre-malignant lesions to invasive carcinomas and distant metastases. Activated K-Ras may therefore not only promote tumor initiation, but also tumor progression and metastasis formation. Metastasis formation is a very complex and inefficient process: Tumor cells have to disseminate from the primary tumor, invade the local stroma to gain access to the vasculature (intravasation), survive in the hostile environment of the circulation and the distant microvascular beds, gain access to the distant parenchyma (extravasation) and survive and grow out in this new environment. In this review, we discuss the potential influence of mutant K-Ras on each of these phases. Furthermore, we have evaluated the clinical evidence that suggests a role for K-Ras in the formation of colorectal metastases.
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PMID:Control of colorectal metastasis formation by K-Ras. 1609 78

We have shown previously that Pten deletion leads to the expansion of subset of prostate cancer cells positive for CK5 and p63. Although this subpopulation may be involved in tumor initiation or progression, studies to date have not functionally validated this hypothesis. Using in vitro sphere-forming assay and in vivo prostate reconstitution assay, we show here the presence of a tumor-initiating subpopulation in the Pten prostate cancer mouse model. Specifically, we show that the Lin(-)Sca-1(+)CD49f(high) (LSC) subpopulation overlaps with CK5(+);p63(+) cells and is significantly increased during prostate cancer initiation and progression and after castration. Mutant spheres mimic the structural organization of the epithelial compartment in the Pten-null primary tumor. Sorted LSC cells from either Pten-null spheres or primary tumors are able to regenerate prostate epithelial structure with cancerous morphology, closely mimicking that of primary cancers. Therefore, the LSC subpopulation is capable of initiating a cancerous phenotype that recapitulates the pathology seen in the primary lesions of the Pten mutant prostate model.
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PMID:Lin-Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. 1988 4

Normal tissue homeostasis is maintained through asymmetric cell divisions that produce daughter cells with differing self-renewal and differentiation potentials. Certain tumor cell subfractions can self-renew and repopulate the heterogeneous tumor bulk, suggestive of asymmetric cell division, but an equally plausible explanation is that daughter cells of a symmetric division subsequently adopt differing cell fates. Cosegregation of template DNA during mitosis is one mechanism by which cellular components are segregated asymmetrically during cell division in fibroblast, muscle, mammary, intestinal, and neural cells. Asymmetric cell division of template DNA in tumor cells has remained elusive, however. Through pulse-chase experiments with halogenated thymidine analogs, we determined that a small population of cells within human lung cancer cell lines and primary tumor cell cultures asymmetrically divided their template DNA, which could be visualized in single cells and in real time. Template DNA cosegregation was enhanced by cell-cell contact. Its frequency was density-dependent and modulated by environmental changes, including serum deprivation and hypoxia. In addition, we found that isolated CD133(+) lung cancer cells were capable of tumor cell repopulation. Strikingly, during cell division, CD133 cosegregated with the template DNA, whereas the differentiation markers prosurfactant protein-C and pan-cytokeratins were passed to the opposing daughter cell, demonstrating that segregation of template DNA correlates with lung cancer cell fate. Our results demonstrate that human lung tumor cell fate decisions may be regulated during the cell division process. The characterization and modulation of asymmetric cell division in lung cancer can provide insight into tumor initiation, growth, and maintenance.
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PMID:Microenvironmental modulation of asymmetric cell division in human lung cancer cells. 2008 Jun 68

Anoikis is a mode of apoptotic cell death, consequential to insufficient cell-matrix interactions and a critical player in tumor angiogenesis and metastasis. The events involved in tumor cell progression toward metastasis potential are mediated by integrins, which upon engagement with components of the extracellular matrix (ECM), reorganize to form adhesion complexes. Targeting apoptotic players is of immense therapeutic significance since resistance to apoptosis is not only critical in conferring therapeutic failure to standard treatment strategies, but anoikis (apoptosis upon loss of anchorage and detachment from ECM) also plays an important role in angiogenesis and metastasis. The ability to survive in the absence of adhesion to the ECM, enables tumor cells to disseminate from the primary tumor site, invade a distant site and establish a metastatic lesion. Tumor cells can escape from detachment-induced apoptosis by controlling anoikis pathways, including the extrinsic death receptor pathway and the ECM-integrin mediated cell survival pathway. Considering the functional promiscuity of individual signaling effectors, it is critical to dissect the molecular networks mechanistically driving tumor cells to evade anoikis and embark on a metastatic spread. Resistance to die via anoikis dictates tumor cell survival and provides a molecular basis for therapeutic targeting of metastatic prostate cancer. Further dissection of critical anoikis signaling events will enable the therapeutic optimization of anoikis targeting to impair prostate cancer metastasis prior to its initiation. This review will discuss the molecular understanding of anoikis regulation in the tumor microenvironment and the in vivo pharmacological implementation of a novel class of antitumor-drugs to optimize apoptotic-based therapeutic targeting, bypassing anoikis-resistance to impair prostate cancer progression to metastasis. Potential combination strategies targeting tumor vascularity (via anoikis) and impairing tumor initiation (via "classic" apoptosis), provide strong therapeutic promise for metastatic prostate cancer by preventing the onset of metastasis.
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PMID:Targeting anoikis resistance in prostate cancer metastasis. 2015 62

The Rip1Tag2 transgenic mouse model of pancreatic beta-cell carcinogenesis has been instrumental in identifying several hallmarks of cancer, including tumor cell evasion from apoptosis, tumor angiogenesis and tumor invasion. Moreover, Rip1Tag2 mice have been helpful in the development and testing of innovative cancer therapies and tumor imaging protocols. However, based on tumor localization in the mouse, primary tumor growth and metastatic dissemination cannot be easily monitored in a longitudinal axis by non-invasive and low-technology approaches. Here, we report the generation of a new transgenic mouse line as a versatile tool to study beta-cell carcinogenesis. Transgenic expression of a bicistronic messenger RNA encoding simian virus large T antigen and firefly luciferase in pancreatic beta-cells recapitulates insulinoma development in a reproducible multistage process. In the mouse line called RipTag-IRES-Luciferase line (RTL) 1, the beta-cell-specific expression of luciferase allows the non-invasive monitoring of primary tumor growth over time in vivo and the detection and quantification of disseminated tumor cells and micrometastases in distant organs ex vivo. When crossed to mouse lines in which the expression of cancer 'modifier' genes has been manipulated, tumor initiation and tumor progression are similarly affected as previously reported for Rip1Tag2 mice, indicating a robust tumor progression pathway shared between the two different transgenic mouse lines. Together, the data indicate that the RTL1 mouse line will be of great value to study anti-tumoral therapeutic approaches as well as to define the functional roles of cancer- and metastasis-related genes when crossed to appropriate transgenic or gene-targeted mouse lines.
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PMID:A bioluminescent mouse model of pancreatic {beta}-cell carcinogenesis. 2053 May 53

One of the major questions in preclinical testing of potential cancer preventive agents is how to most closely approximate the testing protocol to be employed in phase III prevention trials. The nature of tumors arising in situ in animals allows one to initiate agent exposure from the time of tumor initiation until the time that preinvasive lesions already exist. The large phase III prevention trials have routinely followed participants for 3 to 7 years until a cancer endpoint, which generally implies that the timing of the intervention occurs further along during tumor progression. The objective of preclinical testing is to identify agents for large-scale phase III trials. Accordingly, initiating the tested intervention in preclinical studies later in the tumor progression process is more appropriate for any agent being proposed for phase III clinical trials. Furthermore, cancer, rather than advanced dysplastic lesions or other molecular markers (gene or protein expression), is the preferred primary endpoint. However, simultaneous examination of earlier designated "intermediate" endpoints (hyperplasias, dysplasias, or molecular markers) to determine whether their modulation correlates with that of the primary tumor endpoint would be useful, since these latter endpoints may be employed in phase II prevention trials.
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PMID:Further thoughts on preclinical animal models for cancer prevention: when is it best to start treatment? What are potential histopathologic endpoints? 2081 4

Many tumor cells exhibit a disturbed intracellular redox state resulting in higher levels of reactive oxygen species (ROS). As these contribute to tumor initiation and sustenance, catalytic redox agents combining significant activity with substrate specificity promise high activity and selectivity against oxidatively stressed malignant cells. We describe here the design and synthesis of novel organochalcogen based redox sensor/effector catalysts. Their selective anticancer activity at submicromolar and low micromolar concentrations was established here in a range of tumor entities in various biological systems including cell lines, primary tumor cell cultures, and animal models. In the B-cell derived chronic lymphocytic leukemia (CLL), for instance, such compounds preferentially induce apoptosis in the cancer cells while peripheral blood mononuclear cells (PBMC) from healthy donors and the subset of normal B-cells remain largely unaffected. In support of the concept of sensor/effector based ROS amplification, we are able to demonstrate that underlying this selective activity against CLL cells are pre-existing elevated ROS levels in the leukemic cells compared to their nonmalignant counterparts. Furthermore, the catalysts act in concert with certain chemotherapeutic drugs in several carcinoma cell lines to decrease cell proliferation while showing no such interactions in normal cells. Overall, the high efficacy and selectivity of (redox) catalytic sensor/effector compounds warrant further, extensive testing toward transfer into the clinical arena.
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PMID:Synthesis and selective anticancer activity of organochalcogen based redox catalysts. 2083 56


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