Patient-Derived Gastric Carcinoma Xenograft Mouse Models Faithfully Represent Human Tumor Molecular Diversity
Tianwei ZhangLin ZhangShuqiong FanMeizhuo ZhangHaihua FuYuanjie LiuXiaolu YinHao ChenLiang XieJingchuan ZhangPaul R. GavineYi GuXing-zhi NiXinying Su
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Patient-derived cancer xenografts (PDCX) generally represent more reliable models of human disease in which to evaluate a potential drugs preclinical efficacy. However to date, only a few patient-derived gastric cancer xenograft (PDGCX) models have been reported. In this study, we aimed to establish additional PDGCX models and to evaluate whether these models accurately reflected the histological and genetic diversities of the corresponding patient tumors. By engrafting fresh patient gastric cancer (GC) tissues into immune-compromised mice (SCID and/or nude mice), thirty two PDGCX models were established. Histological features were assessed by a qualified pathologist based on H&E staining. Genomic comparison was performed for several biomarkers including ERBB1, ERBB2, ERBB3, FGFR2, MET and PTEN. These biomarkers were profiled to assess gene copy number by fluorescent in situ hybridization (FISH) and/or protein expression by immunohistochemistry (IHC). All 32 PDGCX models retained the histological features of the corresponding human tumors. Furthermore, among the 32 models, 78% (25/32) highly expressed ERBB1 (EGFR), 22% (7/32) were ERBB2 (HER2) positive, 78% (25/32) showed ERBB3 (HER3) high expression, 66% (21/32) lost PTEN expression, 3% (1/32) harbored FGFR2 amplification, 41% (13/32) were positive for MET expression and 16% (5/32) were MET gene amplified. Between the PDGCX models and their parental tumors, a high degree of similarity was observed for FGFR2 and MET gene amplification, and also for ERBB2 status (agreement rate = 94~100%; kappa value = 0.81~1). Protein expression of PTEN and MET also showed moderate agreement (agreement rate = 78%; kappa value = 0.46~0.56), while ERBB1 and ERBB3 expression showed slight agreement (agreement rate = 59~75%; kappa value = 0.18~0.19). ERBB2 positivity, FGFR2 or MET gene amplification was all maintained until passage 12 in mice. The stability of the molecular profiles observed across subsequent passages within the individual models provides confidence in the utility and translational significance of these models for in vivo testing of personalized therapies.Tensin
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PTEN(phosphatase and tensin homolog deleted on chromosome ten)is phosphatase specificity and can inhibit oncogenesis.The mutation and loss of PTEN is the oncogenesis basis of all kinds of tumor,including urinary system tumor.Studies show that mutation and loss of PTEN,which can lead to the dysfunction of tumor suppress,induced oncogenesis of renal cell carcinoma,bladder carcinoma and prostatic carcinoma,revealling that PTEN can inhibit tumorigenesis of urnary system.But the detail of the mutation and loss of PTEN and how PTEN inhibit tumorigensis are still unclear,further study is warranted.
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New therapeutic strategies are needed to improve survival in glioblastoma (GBM) the most malignant astrocytic tumor. We evaluated: a) the genetic status of 22 GBMs by comparative genomic hybridization (CGH); b) the specific role of mutation and/or homozygous deletion of PTEN in the genesis of GBM; and c) the possible therapeutic role of PTEN against GBM, in vitro. CGH demonstrated that the most frequent region of gain was at chromosome 7p, whereas the most frequent losses occurred at chromosomes 10q and 13q. Losses at chromosome 10 were found in 36% of patients, and PTEN was mutated in 27% of the 22 GBMs, including 4 point mutations and 2 homozygous deletions. The possible therapeutic role of PTEN in GBM was also studied in a system based on retroviral infection of the GBM cell line A172, homozygously deleted at the PTEN locus. A172 growth and proliferation rate were reduced by 50% after PTEN transduction. Moreover, we showed that inhibition of cell growth occurred through the PI3K/Akt/p27 pathway. Our findings suggest that PTEN participates in the genesis of GBM, and might be further studied as a candidate therapeutic agent in other testing systems.
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Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor commonly inactivated in glioblastoma multiforme (GBM), but the prognostic significance of PTEN remains controversial. Here, we demon- strate significant prognostic value of combined PTEN mutation and expression for the survival of patients with GBM on the basis of analysis of large-scale cancer genomic data. PTEN nonsense mutations associated with sig- nificantly shorter disease-free survival and overexpression of PTEN protein linked to shorter disease-free and overall survival of patients with GBM. PTEN nonsense mutations correlated with decreased p53 and Gata3 protein levels and increased genomic instability in human GBM tissues. Expression of nonsense PTEN mutant decreased p53 and Gata3 levels, producing increased DNA damage both in vitro and in vivo. Mice carrying xenograft tumors with nonsense PTEN mutant displayed significantly shorter survival. Our data demonstrated the prognostic value of combined PTEN mutation and protein expression for patients with GBM and highlighted distinct biologic effects of nonsense and missense mutations of PTEN.
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Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is widely known as a tumor suppressor gene. It is located on chromosome 10q23 with 200 kb, and has dual activity of both protein and lipid phosphatase. In addition, as a targeted gene in multiple pathways, PTEN has a variety of physiological activities, such as those regulating the cell cycle, inducing cell apoptosis, and inhibiting cell invasion, etc. The PTEN gene have been identified in many kinds of cancers due to its mutations, deletions and inactivation, such as lung cancer, liver cancer, and breast cancer, and they are closely connected with the genesis and progression of cancers. To a large extent, the tumor suppressive function of PTEN is realized through its inhibition of the PI3K/AKT signaling pathway which controls cells apoptosis and development. In addition, PTEN loss has been associated with the prognosis of many cancers, such as lung cancer, liver cancer, and breast cancer. PTEN gene is related to many cancers and their pathological development. On the basis of a large number of related studies, this study describes in detail the structure, regulation, function and classical signal pathways of PTEN, as well as the relationship between various tumors related to PTEN. In addition, some drug studies targeting PTEN/PI3K/AKT/mTOR are also introduced in order to provide some directions for experimental research and clinical treatment of tumors.
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Tumor suppressors function in a coordinated regulatory network, and their inactivation is a key step in carcinogenesis. The tumor suppressor Par-4 is a novel integral player in the PTEN network. Thus, Par-4 is absent in a high percentage of human prostate carcinomas, and its loss is concomitantly associated with PTEN loss. Genetic ablation of Par-4 induces fully invasive prostate carcinomas in PTEN-heterozygous mice. In contrast, Par-4 deficiency alone, like PTEN heterozygosis, results in lesions that are unable to progress beyond the benign neoplastic stage known as PIN. At this PIN transition, the mutual induction of Par-4 and PTEN is an additional regulatory step in preventing cancer progression. Par-4 deficiency cooperates with PTEN haploinsufficiency in prostate cancer initiation and progression and their simultaneous inactivation, in addition to enhancing Akt activation, sets in motion a unique mechanism involving the synergistic activation of NF-κB. These results suggest that the concurrent interruption of complementary signaling pathways targeting PI3K/Akt and NF-κB activation could provide new and effective strategies for cancer therapy.
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PTEN and PIK3CA mutations occur with high frequency in uterine endometrioid carcinoma (UEC). Although PTEN mutations are present in complex atypical hyperplasia and carcinoma, PIK3CA mutations are restricted to carcinoma. We generated mouse models harboring Pten loss and/or activated Pik3ca in the endometrial epithelium to investigate their respective roles in the pathogenesis of UEC. Presence of an activated mutant Pik3ca on the background of Pten loss led to aggressive disease, with 100% of mice exhibiting carcinoma. Expression of Pik3ca with E545K mutation alone was unable to cause hyperplasia or cancer in the uterus and did not activate Akt as effectively as Pten deletion in short-term cultures of mouse endometrial epithelium, likely explaining the lack of phenotype in vivo. We also report that nuclear localization of FOXO1 correlated with PTEN mutational status irrespective of the PIK3CA status in endometrial cancer cell lines. Furthermore, gene expression profiles resulting from Pten loss or activation of Pik3ca in primary mouse endometrial epithelial cells exhibit minimal overlap. Thus, Pten and Pik3ca have distinct consequences on the activation of the phosphatidylinositol 3-kinase pathway in endometrial epithelium and are likely to affect other nonoverlapping cellular mechanisms involved in the development and progression of the most common type of uterine cancer.
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Abstract Objective Esophageal squamous cell carcinoma (ESCC) is featured by early metastasis and late diagnosis. MicroRNA-301 (miR-301) is known to participate in diverse cancers. Nevertheless, effects of miR-301 on ESCC remain unexplored. Thus, we aim to explore the role of miR-301 in ESCC progression. Methods Expression of miR-301 and phosphatase and tensin homologue (PTEN) in ESCC tissues and cell lines was assessed. Next, the screened cells were treated with altered miR-301 or PTEN oligonucleotide and plasmid, and then, the colony formation ability, cell viability, migration, invasion, cell cycle distribution and apoptosis of ESCC cells were assessed. Moreover, tumor growth and microvessel density (MVD) were also assessed, and the targeting relationship between miR-301 and PTEN was affirmed. Results MiR-301 was upregulated, and PTEN was downregulated in ESCC tissues and cells. KYSE30 cells and Eca109 cells were selected for functional assays. In KYSE30 cells, inhibited miR-301 or overexpressed PTEN suppressed cell malignant behaviors, and silenced PTEN eliminated the impact of miR-301 inhibition on ESCC progression. In Eca109 cells, miR-301 overexpression or PTEN inhibition promoted cell malignant behaviors, and PTEN overexpression reversed the effects of miR-301 elevation on ESCC progression. The in vivo assay revealed that miR-301 inhibition or PTEN overexpression repressed ESCC tumor growth and MVD, and miR-301 elevation or PTEN reduction had contrary effects. Moreover, PTEN was targeted by miR-301. Conclusion Taken together, results in our study revealed that miR-301 affected cell growth, metastasis and angiogenesis via regulating PTEN expression in ESCC.
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