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)

PTEN mutations are among the most frequent genetic alterations found in human prostate cancers. Our previous works suggest that although precancerous lesions were found in Pten heterozygous mice, cancer progression and metastasis only happened when both alleles of Pten were deleted. To understand the molecular mechanisms underlying the role of PTEN in prostate cancer control, we generated two pairs of isogenic, androgen receptor (AR)-positive prostate epithelial lines from intact conditional Pten knock-out mice that are either heterozygous (PTEN-P2 and -P8) or homozygous (PTEN-CaP2 and PTEN-CaP8) for Pten deletion. Further characterization of these cells showed that loss of the second allele of Pten leads to increased anchorage-independent growth in vitro and tumorigenesis in vivo without obvious structural or numerical chromosome changes based on SKY karyotyping analysis. Despite no prior exposure to hormone ablation therapy, Pten null cells are tumorigenic in both male and female severe combined immunodeficiency mice. Furthermore, knocking down PTEN can convert the androgen-dependent Myc-CaP cell into androgen independence, suggesting that PTEN intrinsically controls androgen responsiveness, a critical step in the development of hormone refractory prostate cancer. Importantly, knocking down AR by shRNA in Pten null cells reverses androgen-independent growth in vitro and partially inhibited tumorigenesis in vivo, indicating that PTEN-controlled prostate tumorigenesis is AR dependent. These cell lines will serve as useful tools for understanding signaling pathways controlled by PTEN and elucidating the molecular mechanisms involved in hormone refractory prostate cancer formation.
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PMID:Murine cell lines derived from Pten null prostate cancer show the critical role of PTEN in hormone refractory prostate cancer development. 1761 63

Loss of HLA class I expression on tumor cells is a frequent event as an immune escape mechanism. Seven different altered HLA phenotypes have been defined in tumors. Various molecular mechanisms have been described as responsible for HLA class I loss. HLA class I expression alterations occur successively and unpredictably during tumor progression in vivo and immunoselection has been implicated in this process. We present an experimental xenograft model in which melanoma cell line Ando-2 injected into athymic nude mice lost total surface HLA class I expression and exhibited HLA class II cell surface expression. A strong down-regulation of HLA class I expression and de novo HLA class II expression were also found when Ando-2 melanoma cells were injected into SCID-Beige mice. These phenomena were reproducible and were only observed in local growth in nude or SCID-Beige mice and not in vitro after multiple passages. HLA class I surface expression was recovered after IFN-gamma treatment, indicating regulatory defects. The mechanism implicated in loss of HLA class I molecule expression were a down-regulation of different components of antigen processing machinery and HLA class I heavy chains. These data suggest that HLA class I alterations can also occur in absence of autologous adaptive immune response. This is a good experimental in vivo model to study the relationship between tumor progression and HLA class I alterations.
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PMID:Total loss of HLA class I expression on a melanoma cell line after growth in nude mice in absence of autologous antitumor immune response. 1762 28

A considerable amount of evidence has established that gap junctional intercellular communication (GJIC) suppresses tumor development by halting the stage of tumor promotion. Consistently, GJIC is downregulated in tumors. The downregulation of GJIC is caused by not only the reduced expression level of connexin proteins but also their aberrant cytoplasmic localization. Although it has long been thought that cytoplasmic localization of connexin proteins is merely one of the mechanisms of the downregulation of GJIC, careful studies with human tumor samples have indicated that the expression level of intracytoplasmic connexin proteins correlates well with the grade of malignancy and the progression stage of tumors. Hypothesizing that intracytoplasmic connexin proteins should have their proper functions and that their increase should facilitate tumor progression such as cell migration, invasion and metastasis, we examined the effects of overexpressed connexin32 (Cx32) protein on the phenotype of human HuH7 hepatoma cells, which express a basal level of endogenous Cx32 only in cytoplasm. The cells were retrovirally transduced with the Tet-off Cx32 construct so that withdrawal of doxycycline from the culture medium could induce overexpression of Cx32 protein in cytoplasm. Even when overexpressed, Cx32 protein was retained in cytoplasm, i.e., Golgi apparatuses, and did not induce GJIC. However, overexpression of Cx32 protein in cytoplasm enhanced both the motility and the invasiveness of HuH7 cells and induced metastasis when the cells were xenografted into SCID mice. Taken together, cytoplasmic accumulation of connexin proteins may exert effects favorable for tumor progression.
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PMID:Pathological significance of intracytoplasmic connexin proteins: implication in tumor progression. 1765 24

Tumors that acquire resistance against death stimuli constitute a severe problem in the context of cancer therapy. To determine genetic alterations that favor the development of stress-resistant tumors in vivo, we took advantage of polyclonal tumors generated after retroviral infection of newborn Elambda-MYC mice, in which the retroviral integration acts as a mutagen to enhance tumor progression. Tumor cells were cultivated ex vivo and exposed to gamma-irradiation prior to their transplantation into syngenic recipients, thereby providing a strong selective pressure for pro-survival mutations. Secondary tumors developing from stress-resistant tumor stem cells were analysed for retroviral integration sites to reveal candidate genes whose dysregulation confer survival. In addition to the gene encoding the antiapoptotic Bcl-x(L) protein, we identified the gadd45b locus to be a novel common integration site in these tumors, leading to enhanced expression. In accord with a thus far undocumented role of Gadd45beta in tumorigenesis, we showed that NIH3T3 cells overexpressing Gadd45beta form tumors in NOD/SCID mice. Interestingly and differently to other known 'classical' antiapoptotic factors, high Gadd45beta levels did not protect against MYC-, UV- or gamma-irradiation-induced apoptosis, but conferred a strong and specific survival advantage to serum withdrawal.
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PMID:Gadd45 beta is a pro-survival factor associated with stress-resistant tumors. 1789 Nov 84

The most prevalent mutations associated with the development of clear-cell renal cell carcinoma (CC-RCC) are the loss-of-function mutations of von Hippel-Lindau (VHL) tumor suppressor gene. These mutations invariably result in an inappropriate accumulation of HIF-alpha due to a failure of VHL as a substrate-recognition component of an E3 ubiquitin ligase complex to target HIFalpha for oxygen-dependent ubiquitin-mediated destruction. Stabilization of HIF-2alpha, but not HIF-1alpha, is the critical oncogenic event upon the functional loss of VHL in the development of CC-RCC. Here, we show that HIF-3alpha4, an alternatively spliced variant of human HIF-3alpha with similar domain structure as the murine inhibitory PAS protein (IPAS), forms an abortive transcriptional complex with HIF-2alpha and prevents the engagement of HIF-2 to the hypoxia-responsive elements (HREs) located in the promoter/ enhancer regions of hypoxia-inducible genes. In addition, the re-expression of HIF-3alpha4 in VHL-null 786-O CC-RCC cells via adenovirus decreases the endogenous expression of HIF-2-driven gene expression and suppresses the growth of 786-O tumor xenografts in SCID mice. These results suggest that HIF-3alpha4 is a naturally occurring dominant-negative HIF-3alpha splice isoform with tumor suppressive activity and support the targeted delivery of HIF-3alpha4 as a potential therapeutic option to curtail HIF-dependent tumor progression.
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PMID:Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression. 1799 5

Members of the aspartic protease family have been implicated in cancer progression. The aspartic protease napsin A is expressed in type II cells of the lung, where it is involved in the processing of surfactant protein B (SP-B). Napsin A is also expressed in kidney, where its function is unknown. Here, we examined napsin A mRNA expression in human kidney tissues using in situ hybridization. Whereas strong napsin A mRNA expression was observed in kidney proximal tubules, expression was detected in only one of 29 renal cell carcinomas. This result is consistent with previous observations of loss of napsin A expression in high-grade lung adenocarcinomas. We re-expressed napsin A in the tumorigenic HEK293 kidney cell line and examined the phenotype of stably transfected cells. Napsin A-expressing HEK293 cells showed an altered phenotype characterized by formation of cyst-like structures in three-dimensional collagen cultures. Napsin A-expressing cells also showed reduced capacity for anchorage-independent growth and formed tumors in SCID mice with a lower efficiency and slower onset compared to vector-transfected control cells. Mutation of one of the aspartic acid residues in the napsin A catalytic site inactivated enzymatic activity, but did not influence the ability to suppress colony formation in soft agar and tumor formation. The mutation of the catalytic site did not affect processing, glycosylation or intracellular localization of napsin A. These data show that napsin A inhibits tumor growth of HEK293 cells by a mechanism independent of its catalytic activity.
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PMID:The aspartic protease napsin A suppresses tumor growth independent of its catalytic activity. 1819 89

CaSm (cancer-associated Sm-like) was originally identified based on elevated expression in pancreatic cancer and in several cancer-derived cell lines. It encodes a 133-amino acid protein that contains two Sm motifs found in the common snRNP proteins and the LSm (like-Sm) family of proteins. Lung tumors and mesotheliomas express high levels of CaSm mRNA and protein compared with adjacent nontumor and normal lung tissue, measured by immunohistochemistry, qRT-PCR, and Western blot analyses. In addition, several human lung cancer- and mesothelioma-derived cell lines have elevated CaSm expression. Two cell lines, transfected with and expressing antisense CaSm RNA, demonstrate altered transformed phenotypes, reducing their ability to form colonies in soft agar and tumors in SCID mice. Furthermore, RNAi-mediated reduction of CaSm RNA and protein is associated with inhibition of cellular growth. These data support the model that elevated CaSm expression in epithelial tissue contributes to the transformed state. Cell lines expressing exogenous CaSm also exhibit transformed characteristics, including increased anchorage-independent colony formation and tumor growth. Thus, the results of loss of function and gain of function studies presented both indicate that CaSm functions as an oncogene in the promotion of cellular transformation and cancer progression.
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PMID:CaSm (LSm-1) overexpression in lung cancer and mesothelioma is required for transformed phenotypes. 1821 95

The majority of human malignancies are believed to have epithelial origin, and the progression of cancer is often associated with a transient process named epithelial-mesenchymal transition (EMT). EMT is characterized by the loss of epithelial markers and the gain of mesenchymal markers that are typical of "cancer stem-like cells," which results in increased cell invasion and metastasis in vivo. Therefore, it is important to uncover the mechanistic role of factors that may induce EMT in cancer progression. Studies have shown that platelet-derived growth factor (PDGF) signaling contributes to EMT, and more recently, PDGF-D has been shown to regulate cancer cell invasion and angiogenesis. However, the mechanism by which PDGF-D promotes invasion and metastases and whether it is due to the acquisition of EMT phenotype remain elusive. For this study, we established stably transfected PC3 cells expressing high levels of PDGF-D, which resulted in the significant induction of EMT as shown by changes in cellular morphology concomitant with the loss of E-cadherin and zonula occludens-1 and gain of vimentin. We also found activation of mammalian target of rapamycin and nuclear factor-kappaB, as well as Bcl-2 overexpression, in PDGF-D PC3 cells, which was associated with enhanced adhesive and invasive behaviors. More importantly, PDGF-D-overexpressing PC3 cells showed tumor growth in SCID mice much more rapidly than PC3 cells. These results provided a novel mechanism by which PDGF-D promotes EMT, which in turn increases tumor growth, and these results further suggest that PDGF-D could be a novel therapeutic target for the prevention and/or treatment of prostate cancer. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. 1840 54

Thrombospondin (TSP)-1, a potent angiogenesis inhibitor, has been shown to exert different biological functions on various cell types. Here, we investigate the role of TSP-1 in tumor-stroma reaction, which is mainly characterized by fibroblast activation to create a permissive microenvironment for tumor progression. Immunohistochemistry examinations in the human surgical specimens have shown that a downregulation of TSP-1 during the progression of cervical carcinogenesis was accompanied by an emergence in the upregulation of stroma markers, alpha-smooth muscle actin (alpha-SMA) and desmin. Transfection of SiHa cervical cancer cells with a plasmid expressing the TSP-1 protein exhibited antiangiogenic activity in vitro and resulted in reduced tumor growth in severe combined immunodeficiency (SCID) mice, which was accompanied by a decrease in tumor vascularization and lower expressions of alpha-SMA and desmin than those in the vector controls. Transfection with TSP-1 and purified TSP-1 added to NIH3T3 cells did not alter the protein levels of alpha-SMA and desmin but significantly inhibited matrix metalloprotease-2 activity. Transforming growth factor-beta (TGF-beta), a major factor in the activation of fibroblasts, increased alpha-SMA and desmin expression and the ability of cell migration and invasion in NIH3T3 cells. The increased migration ability and the invasive ability into tumor cluster of TGF-beta-treated NIH3T3 cells were dose dependently inhibited by TSP-1. In contrast, ectopic TSP-1 expression in SiHa cells has little effect on the invasive ability of the NIH3T3 cells. Together, our findings demonstrate a novel role of TSP-1 to inhibit tumor-stroma reaction that could be attributed to the blockage of activated fibroblasts from invading cancer cells.
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PMID:A novel role of thrombospondin-1 in cervical carcinogenesis: inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer. 1841 67

B7-H4, a newly discovered member of B7 family that negatively regulates T cell-mediated immunity, may facilitate tumor progression by undermining host immunity. Recent studies show that brain tumor stem-like cells (TSCs) contribute to tumorigenesis. However, the relationship between B7-H4 and the clinical behavior of brain TSCs remains unclear. In this study, we found that B7-H4 was expressed in cultured tumor cells from human gliomas (n = 5) and medulloblastomas (n = 3). Double immunostaining indicated that B7-H4 was primarily restricted to non-dividing (Ki67(-)) cultured tumor cells. Tumor cells cultured under medium conditions favoring the growth of neural stem cells were able to form primary and secondary spheres, along with expression of neural stem/progenitor cell markers. These cells differentiated into different neural lineages when cultured in differentiation medium, indicating that these cells have TSCs characteristics. Double immunostaining showed that TSCs consisted of proliferative (Ki67(+)) and quiescent (Ki67(-)) cells. We also found that B7-H4 was expressed in a small population of CD133(+) cells sorted by flow cytometry. Interestingly, both CD133(+) and CD133(-) cells were tumorigenic in SCID mice in vivo. However, CD133(+) cells-initiated glioblastomas showed a higher proliferation index, compared to CD133(-) cells-induced glioblastomas in vivo. Secondary glioma cells derived from CD133(+) or CD133(-) cell xenografts expressed B7-H4 as well. Our data suggest B7-H4 is preferentially expressed in non-dividing brain tumor cells and in a subpopulation of brain TSCs, and CD133(-) tumor cells also have the capacity to initiate brain formation in vivo.
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PMID:B7-H4 is preferentially expressed in non-dividing brain tumor cells and in a subset of brain tumor stem-like cells. 1847 83


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