RESUMO
Serous endometrial carcinoma (SEC) constitutes about 10% of endometrial carcinomas and is one of the most aggressive and lethal types of uterine cancer. Due to the rapid progression of SEC, early detection of this disease is of utmost importance. However, molecular and cellular dynamics during the pre-dysplastic stage of this disease remain largely unknown. Here, we provide a comprehensive census of cell types and their states for normal, pre-dysplastic, and dysplastic endometrium in a mouse model of SEC. This model is associated with inactivation of tumor suppressor genes Trp53 and Rb1 , whose pathways are altered frequently in SEC. We report that pre-dysplastic changes are characterized by an expanded and increasingly diverse immature luminal epithelial cell populations. Consistent with transcriptome changes, cells expressing the luminal epithelial marker TROP2 begin to substitute FOXA2+ cells in the glandular epithelium. These changes are associated with a reduction in number and strength of predicted interactions between epithelial and stromal endometrial cells. By using a multi-level approach combining single-cell and spatial transcriptomics paired with screening for clinically relevant genes in human endometrial carcinoma, we identified a panel of 44 genes suitable for further testing of their validity as early diagnostic and prognostic markers. Among these genes are known markers of human SEC, such as C DKN2A, and novel markers, such as OAS2 and OASL, members of 2-5A synthetase family that is essential for the innate immune response. In summary, our results suggest an important role of the luminal epithelium in SEC pathogenesis, highlight aberrant cell-cell interactions in pre-dysplastic stages, and provide a new platform for comparative identification and characterization of novel, clinically relevant prognostic and diagnostic markers and potential therapeutic modalities.
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Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. AMP-activated protein kinase (AMPK) is a master regulator of metabolism, although its role in PCa remains unclear. Here, we show that genetic and pharmacological activation of AMPK provides a protective effect on PCa progression in vivo. We show that AMPK activation induces PGC1α expression, leading to catabolic metabolic reprogramming of PCa cells. This catabolic state is characterized by increased mitochondrial gene expression, increased fatty acid oxidation, decreased lipogenic potential, decreased cell proliferation, and decreased cell invasiveness. Together, these changes inhibit PCa disease progression. Additionally, we identify a gene network involved in cell cycle regulation that is inhibited by AMPK activation. Strikingly, we show a correlation between this gene network and PGC1α gene expression in human PCa. Taken together, our findings support the use of AMPK activators for clinical treatment of PCa to improve patient outcome.
Assuntos
Proteínas Quinases Ativadas por AMP , Neoplasias da Próstata , Masculino , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Lipogênese , Metabolismo dos Lipídeos , Neoplasias da Próstata/patologiaRESUMO
Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells, but their location and hierarchy remain debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported that this tissue can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Here, we describe a single-cell transcriptomic atlas of the main cell types of the mouse uterus and epithelial subset transcriptome and evaluate the contribution of epithelial cells expressing the transcription factor PAX8 to the homeostatic regeneration and malignant transformation of adult endometrial epithelium. According to lineage tracing, PAX8+ epithelial cells are responsible for long-term maintenance of both luminal and glandular epithelium. Furthermore, multicolor tracing shows that individual glands and contiguous areas of luminal epithelium are formed by clonal cell expansion. Inactivation of the tumor suppressor genes Trp53 and Rb1 in PAX8+ cells, but not in FOXJ1+ cells, leads to the formation of neoplasms with features of serous endometrial carcinoma, one of the most aggressive types of human endometrial malignancies. Taken together, our results show that the progeny of single PAX8+ cells represents the main source of regeneration of the adult endometrial epithelium. They also provide direct experimental genetic evidence for the key roles of the P53 and RB pathways in the pathogenesis of serous endometrial carcinoma and suggest that PAX8+ cells represent the cell of origin of this neoplasm.
Assuntos
Neoplasias do Endométrio/patologia , Endométrio/patologia , Epitélio/patologia , Homeostase , Neoplasias Císticas, Mucinosas e Serosas/patologia , Fator de Transcrição PAX8/metabolismo , Regeneração , Envelhecimento , Animais , Proliferação de Células , Modelos Animais de Doenças , Neoplasias do Endométrio/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Imunofenotipagem , Integrases/metabolismo , Camundongos Transgênicos , Neoplasias Císticas, Mucinosas e Serosas/genética , Fator de Transcrição PAX8/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Útero/metabolismoRESUMO
High-grade serous ovarian carcinoma (HGSOC) is the fifth leading cause of cancer-related deaths of women in the United States. Disease-associated mutations have been identified by the Cancer Genome Atlas Research Network. However, aside from mutations in TP53 or the RB1 pathway that are common in HGSOC, the contributions of mutation combinations are unclear. Here, we report CRISPR mutagenesis of 20 putative HGSOC driver genes to identify combinatorial disruptions of genes that transform either ovarian surface epithelium stem cells (OSE-SCs) or non-stem cells (OSE-NSs). Our results support the OSE-SC theory of HGSOC initiation and suggest that most commonly mutated genes in HGSOC have no effect on OSE-SC transformation initiation. Our results indicate that disruption of TP53 and PTEN, combined with RB1 disruption, constitutes a core set of mutations driving efficient transformation in vitro. The combined data may contribute to more accurate modeling of HGSOC development.
Assuntos
Células Epiteliais/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Células-Tronco/metabolismo , Feminino , Humanos , Mutação , Gradação de TumoresRESUMO
Many high-grade serous carcinomas (HGSCs) likely originate in the distal region of the Fallopian tube's epithelium (TE) before metastasizing to the ovary. Unfortunately, molecular mechanisms promoting malignancy in the distal TE are obfuscated, largely due to limited primary human TE gene expression data. Here we report an in depth bioinformatic characterization of 34 primary TE mRNA-seq samples. These samples were prepared from proximal and distal TE regions of 12 normal Fallopian tubes. Samples were segregated based on their aldehyde dehydrogenase (ALDH) activity. Distal cells form organoids with higher frequency and larger size during serial organoid formation assays when compared to proximal cells. Consistent with enrichment for stem/progenitor cells, ALDH+ cells have greater WNT signaling. Comparative evaluation of proximal and distal TE cell population's shows heightened inflammatory signaling in distal differentiated (ALDH-) TE. Furthermore, comparisons of proximal and distal TE cell populations finds that the distal ALDH+ TE cells exhibit pronounced expression of gene sets characteristic of HGSC sub-types. Overall, our study indicates increased organoid forming capacity, WNT/inflammatory signaling, and HGSC signatures underlie differences between distal and proximal regions of the human TE. These findings provide the basis for further mechanistic studies of distal TE susceptibility to the malignant transformation.
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Biologia Computacional , Células Epiteliais/citologia , Tubas Uterinas/citologia , Via de Sinalização Wnt , Aldeído Desidrogenase/metabolismo , Diferenciação Celular , Células Epiteliais/patologia , Tubas Uterinas/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/patologiaRESUMO
Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency and delay growth of human prostate cancer xenografts by reducing the number of cancer-propagating cells. In sum, our study provides a definitive proof of tumor-suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer-propagating cells in prostate cancers with MME downregulation.
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Areas of a junction between two types of epithelia are known to be cancer-prone in many organ systems. However, mechanisms for preferential malignant transformation at the junction areas remain insufficiently elucidated. Here we report that inactivation of tumor suppressor genes Trp53 and Rb1 in the gastric squamous-columnar junction (SCJ) epithelium results in preferential formation of metastatic poorly differentiated neoplasms, which are similar to human gastroesophageal carcinoma. Unlike transformation-resistant antral cells, SCJ cells contain a highly proliferative pool of immature Lgr5-CD44+ cells, which are prone to transformation in organoid assays, comprise early dysplastic lesions, and constitute up to 30% of all neoplastic cells. CD44 ligand osteopontin (OPN) is preferentially expressed in and promotes organoid formation ability and transformation of the SCJ glandular epithelium. OPN and CD44 overexpression correlate with the worst prognosis of human gastroesophageal carcinoma. Thus, detection and selective targeting of the active OPN-CD44 pathway may have direct clinical relevance.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Junção Esofagogástrica/metabolismo , Receptores de Hialuronatos/metabolismo , Osteopontina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Gástricas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica , Estudos de Coortes , Junção Esofagogástrica/patologia , Feminino , Humanos , Receptores de Hialuronatos/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Osteopontina/genética , Receptores Acoplados a Proteínas G/genética , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
The physical microenvironment of tumor cells plays an important role in cancer initiation and progression. Here, we present evidence that confinement - a new physical parameter that is apart from matrix stiffness - can also induce malignant transformation in mammary epithelial cells. We discovered that MCF10A cells, a benign mammary cell line that forms growth-arrested polarized acini in Matrigel, transforms into cancer-like cells within the same Matrigel material following confinement in alginate shell hydrogel microcapsules. The confined cells exhibited a range of tumor-like behaviors, including uncontrolled cellular proliferation and invasion. Additionally, 4-6 weeks after transplantation into the mammary fad pads of immunocompromised mice, the confined cells formed large palpable masses that exhibited histological features similar to that of carcinomas. Taken together, our findings suggest that physical confinement represents a previously unrecognized mechanism for malignancy induction in mammary epithelial cells and also provide a new, microcapsule-based, high throughput model system for testing new breast cancer therapeutics.
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Transformação Celular Neoplásica/patologia , Células Epiteliais/patologia , Glândulas Mamárias Humanas/patologia , Células Acinares/patologia , Animais , Cápsulas , Carcinogênese/patologia , Matriz Extracelular/metabolismo , Feminino , Humanos , Hidrogéis/química , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos SCID , Análise de Sequência de RNA , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
: New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of AMP-activated protein kinase (Ampk) ß1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer. SIGNIFICANCE: These findings show that CAMKK2 and its downstream target AMPK have opposing effects on prostate cancer development and raise the possibility of a new combined therapeutic approach that inhibits CAMKK2 and activates AMPK.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Lipogênese , Neoplasias da Próstata/patologia , Adenocarcinoma/genética , Animais , Benzimidazóis/química , Sistemas CRISPR-Cas , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Feminino , Deleção de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naftalimidas/química , Invasividade Neoplásica , Fosforilação , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Transdução de SinaisRESUMO
Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and the development of new diagnostic, prognostic, and treatment approaches. Many stem cell niches are well defined anatomically, thereby allowing their routine pathological evaluation during disease initiation and progression. Evaluation of the consequences of genetic manipulations in stem cells and investigation of the roles of stem cells in regenerative medicine and pathogenesis of various diseases such as cancer require significant expertise in pathology for accurate interpretation of novel findings. Therefore, there is an urgent need for developing stem cell pathology as a discipline to facilitate stem cell research and regenerative medicine. This review provides examples of anatomically defined niches suitable for evaluation by diagnostic pathologists, describes neoplastic lesions associated with them, and discusses further directions of stem cell pathology.
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Medicina Regenerativa , Nicho de Células-Tronco , Células-Tronco/patologia , Humanos , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Recently it has been reported that serous tubal intraepithelial carcinoma (STIC), the likely precursor of ovarian/extra-uterine high-grade serous carcinoma, are frequently located in the vicinity of tubal-peritoneal junctions, consistent with the cancer-prone features of many epithelial transitional regions. To test if p53 (aka TP53)-signatures and secretory cell outgrowths (SCOUTs) also localize to tubal-peritoneal junctions, we examined these lesions in the fallopian tubes of patients undergoing salpingo-oophorectomy for sporadic high-grade serous carcinomas or as a prophylactic procedure for carriers of familial BRCA1 or 2 mutations. STICs were located closest to the tubal-peritoneal junctions with an average distance of 1.31 mm, while SCOUTs were not detected in the fimbriated end of the fallopian tube. As many epithelial transitional regions contain stem cells, we also determined the expression of stem cell markers in the normal fallopian tube, tubal intraepithelial lesions and high-grade serous carcinomas. Of those, LEF1 was consistently expressed in the tubal-peritoneal junctions and all lesions, independent of p53 status. All SCOUTs demonstrated strong nuclear expression of ß-catenin consistent with the LEF1 participation in the canonical WNT pathway. However, ß-catenin was preferentially located in the cytoplasm of cells comprising STICs and p53 signatures, suggesting WNT-independent function of LEF1 in those lesions. Both frequency of LEF1 expression and ß-catenin nuclear expression correlated with the worst 5-year patient survival, supporting important role of both proteins in high-grade serous carcinoma. Taken together, our findings suggest the existence of stem cell niche within the tubal-peritoneal junctions. Furthermore, they support the notion that the pathogenesis of SCOUTs is distinct from that of STICs and p53 signatures. The location and discrete patterns of LEF1 and ß-catenin expression may serve as highly sensitive and reliable ancillary markers for the detection and differential diagnosis of tubal intraepithelial lesions.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma in Situ/química , Neoplasias das Tubas Uterinas/química , Fator 1 de Ligação ao Facilitador Linfoide/análise , Células-Tronco Neoplásicas/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Carcinoma in Situ/cirurgia , Estudos de Casos e Controles , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Células-Tronco Neoplásicas/patologia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Salpingo-Ooforectomia , Nicho de Células-Tronco , Fatores de Tempo , Resultado do Tratamento , Microambiente Tumoral , Proteína Supressora de Tumor p53/análise , beta Catenina/análiseRESUMO
Orthotopic transplantation assays in mice are invaluable for studies of cell regeneration and neoplastic transformation. Common approaches for orthotopic transplantation of ovarian surface and tubal epithelia include intraperitoneal and intrabursal administration of cells. The respective limitations of these methods include poorly defined location of injected cells and limited space volume. Furthermore, they are poorly suited for long-term structural preservation of transplanted organs. To address these challenges, we have developed an alternative approach, which is based on the introduction of cells and tissue fragments into the mouse fat pad. The mouse ovarian fat pad is located in the immediate vicinity of the ovary and uterine tube (aka oviduct, fallopian tube), and provides a familiar microenvironment for cells and tissues of these organs. In our approach fluorescence-labeled mouse and human cells, and fragments of the uterine tube are engrafted by using minimally traumatic dorsal incision surgery. Transplanted cells and their outgrowths are easily located in the ovarian fat pad for over 40 days. Long-term transplantation of the entire uterine tube allows correct preservation of all principle tissue components, and does not result in adverse side effects, such as fibrosis and inflammation. Our approach should be uniquely applicable for answering important biological questions such as differentiation, regenerative and neoplastic potential of specific cell populations. Furthermore, it should be suitable for studies of microenvironmental factors in normal development and cancer.
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Tecido Adiposo/transplante , Transplante de Órgãos/veterinária , Ovário/transplante , Animais , Diferenciação Celular , Transformação Celular Neoplásica , Epitélio , Tubas Uterinas , Feminino , Humanos , CamundongosAssuntos
Mama , Neoplasias Ovarianas , Animais , Neoplasias da Mama , Feminino , Humanos , CamundongosRESUMO
BACKGROUND: The majority of newly diagnosed prostate cancers will remain indolent, but distinguishing between aggressive and indolent disease is imprecise. This has led to the important clinical problem of overtreatment. THOC1 encodes a nuclear ribonucleoprotein whose expression is higher in some cancers than in normal tissue. The hypothesis that THOC1 may be a functionally relevant biomarker that can improve the identification of aggressive prostate cancer has not been tested. METHODS: THOC1 protein immunostaining was evaluated in a retrospective collection of more than 700 human prostate cancer specimens and the results associated with clinical variables and outcome. Thoc1 was conditionally deleted in an autochthonous mouse model (n = 22 or 23 per genotype) to test whether it is required for prostate cancer progression. All statistical tests were two-sided. RESULTS: THOC1 protein immunostaining increases with higher Gleason score and more advanced Tumor/Node/Metastasis stage. Time to biochemical recurrence is statistically significantly shorter for cancers with high THOC1 protein (log-rank P = .002, and it remains statistically significantly associated with biochemical recurrence after adjusting for Gleason score, clinical stage, and prostate-specific antigen levels (hazard ratio = 1.61, 95% confidence interval = 1.03 to 2.51, P = .04). Thoc1 deletion prevents prostate cancer progression in mice, but has little effect on normal tissue. Prostate cancer cells deprived of Thoc1 show gene expression defects that compromise cell growth. CONCLUSIONS: Thoc1 is required to support the unique gene expression requirements of aggressive prostate cancer in mice. In humans, high THOC1 protein immunostaining associates with prostate cancer aggressiveness and recurrence. Thus, THOC1 protein is a functionally relevant molecular marker that may improve the identification of aggressive prostate cancers, potentially reducing overtreatment.
Assuntos
Biomarcadores Tumorais/sangue , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Deleção de Genes , Proteínas Nucleares/metabolismo , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas de Ligação a RNA/metabolismo , Animais , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Gradação de Tumores , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Estadiamento de Neoplasias , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Prognóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Proteínas de Ligação a RNA/genética , Estudos Retrospectivos , Análise Serial de TecidosRESUMO
The miR-34 family was originally found to be a direct target of p53 and is a group of putative tumor suppressors. Surprisingly, mice lacking all mir-34 genes show no increase in cancer formation by 18 months of age, hence placing the physiological relevance of previous studies in doubt. Here, we report that mice with prostate epithelium-specific inactivation of mir-34 and p53 show expansion of the prostate stem cell compartment and develop early invasive adenocarcinomas and high-grade prostatic intraepithelial neoplasia, whereas no such lesions are observed after inactivation of either the mir-34 or p53 genes alone by 15 months of age. Consistently, combined deficiency of p53 and miR-34 leads to acceleration of MET-dependent growth, self-renewal, and motility of prostate stem/progenitor cells. Our study provides direct genetic evidence that mir-34 genes are bona fide tumor suppressors and identifies joint control of MET expression by p53 and miR-34 as a key component of prostate stem cell compartment regulation, aberrations in which may lead to cancer.
Assuntos
MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Processos de Crescimento Celular/fisiologia , Masculino , Camundongos , MicroRNAs/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
UNLABELLED: Small cell lung carcinoma (SCLC) is a highly metastatic tumor type with neuroendocrine features and a dismal prognosis. PTEN mutations and PIK3CA activating mutations have been reported in SCLC but the functional relevance of this pathway is unknown. The PTEN/PIK3CA pathway was interrogated using an AdenoCre-driven mouse model of SCLC harboring inactivated Rb and p53. Inactivation of one allele of PTEN in Rb/p53-deleted mice led to accelerated SCLC with frequent metastasis to the liver. In contrast with the high mutation burden reported in human SCLC, exome analyses revealed a low number of protein-altering mutations in mouse SCLC. Inactivation of both alleles of PTEN in the Rb/p53-deleted system led to nonmetastatic adenocarcinoma with neuroendocrine differentiation. This study reveals a critical role for the PTEN/PI3K pathway in both SCLC and lung adenocarcinoma and provides an ideal system to test the phosphoinositide 3-kinase (PI3K) pathway inhibitors as targeted therapy for subsets of patients with SCLC. IMPLICATIONS: The ability of PTEN inactivation to accelerate SCLC in a genetic mouse model suggests that targeting the PTEN pathway is a therapeutic option for a subset of human patients with SCLC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/28/1541-7786.MCR-13-0554/F1.large.jpg.
Assuntos
Neoplasias Pulmonares/genética , PTEN Fosfo-Hidrolase/genética , Carcinoma de Pequenas Células do Pulmão/genética , Animais , Modelos Animais de Doenças , Feminino , Genes Supressores de Tumor , Humanos , Neoplasias Pulmonares/enzimologia , Masculino , Camundongos , PTEN Fosfo-Hidrolase/metabolismo , Carcinoma de Pequenas Células do Pulmão/enzimologiaRESUMO
OBJECTIVE: To evaluate the underlying mechanism of Jianpi Jiedu Recipe (, JJR) in the reversion of multidrug resistance concerning colorectal cancer in vitro and in vivo. METHODS: Mice were treated orally with JJR at a daily 4.25 g/(kg·day) or injected with vinblastine (VCR) 2.5 mg/(kg·day) for 3 weeks after having been inoculated with HCT8/V cells; tumor tissues were assayed by hematoxylin and eosin staining. Firstly, the effects of JJR on the expression of cyclooxygenase-2 (COX-2) were tested by real-time polymerase chain reaction (PCR) technique and COX-2 gene silenced by siRNA. Secondly, the variation of intracellular concentration of oxaliplatin (L-OHP) was evaluated by the inductively coupled plasma mass spectroscopy (ICPMS) in HCT8/V and its COX-2 siRNA cells; the concentration of JJR combined with chemotherapeutic drugs and the reverse effect of multidrug resistance (MDR) in HCT8/V cells was evaluated by the MTT assay. Thirdly, real-time quantitative PCR and Western blot analysis were used to detect the multidrug resistance gene 1 (MDR1) mRNA and P-gp expression. RESULTS: JJR had an inhibitory effect on the growth of tumors in vivo, and it, in combination with chemotherapeutic drugs, could reverse the drug-resistance of HCT8/V cells and increase the sensitivity of HCT8/V cells to VCR, DDP, 5-Fu, and THP. ICP-MS results showed that JJR could increase the concentration of drugs in HCT8/V cells (P<0.01). Furthermore, it was shown that JJR could reverse drug resistance of colorectal cancer cells by decreasing MDR1 expression and P-gp level via downregulation of COX-2, which has been represented as one of the major mechanisms that contributes to the MDR phenotype (P<0.01). CONCLUSION: JJR reversed multidrug resistance and enhanced the sensitivity to chemotherapy, which could be attributed to the down-regulation of COX-2 in MDR1/P-gp-mediated MDR colorectal cancer after chemotherapy.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Ciclo-Oxigenase 2/metabolismo , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 2/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Proteínas de Fluorescência Verde/metabolismo , Humanos , Espaço Intracelular/metabolismo , Camundongos Endogâmicos BALB C , Compostos Organoplatínicos/metabolismo , Oxaliplatina , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vimblastina/farmacologia , Vimblastina/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Recent extensive genomic analyses of epithelial ovarian cancer (EOC), particularly the most common and deadly form of high-grade serous ovarian carcinoma, have provided important insights into the repertoire of molecular aberrations that are characteristic for this malignancy. However, interpretation of the discovered aberrations is complicated because the origin and mechanisms of progression of EOC remain uncertain. Here, we summarize current views on the cell of origin of EOC and discuss recent findings of a cancer-prone stem cell niche for ovarian surface epithelium, one of the major likely sources of EOC. We also outline future directions and challenges in studying the role of stem cell niches in EOC pathogenesis.
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The inhibitor of apoptosis protein survivin is expressed in most cancers. Using the conditional PTEN deletion mouse model, we previously reported that survivin levels increase with prostate tumor growth. Here we evaluated the functional role of survivin in prostate tumor growth. First, we demonstrated that mice lacking the survivin gene in prostate epithelium were fertile and had normal prostate growth and development. We then serially, from about 10-56 weeks of age, evaluated histopathologic changes in the prostate of mice with PTEN deletion combined with survivin mono- or bi-allelic gene deletion. While within this time period most of the animals with wild-type or monoallelic survivin deletion developed adenocarcinomas, the most severe lesions in the biallelic survivin deleted mice were high-grade prostatic intra-epithelial neoplasia with distinct histopathology. Many atypical cells contained large hypertrophic cytoplasm and desmoplastic reaction in the prostatic intra-epithelial neoplasia lesions of this group was minimal until the late ages. A reduced proliferation index as well as apoptotic and senescent cells were detected in the lesions of mice with compound PTEN/survivin deficiency throughout the time points examined. Survivin deletion was also associated with reduced tumor expression of another inhibitor of apoptosis member, the X-linked inhibitor of apoptosis. Our findings suggest that survivin participates in the progression of prostatic intraepithelial neoplasia to adenocarcinoma, and that survivin interference at the prostatic intraepithelial neoplasia stages may be a potential therapeutic strategy to halt or delay further progression.