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BACKGROUND: To evaluate contemporary preoperative risk factors and subsequent postoperative management of incidental prostate cancer (iPCa) and incidental clinically significant prostate cancer (icsPCa, Grade Group [GG] ≥ 2 PCa). METHODS: A retrospective cohort of 811 men undergoing Holmium enucleation of the prostate (HoLEP) (January 2021-July 2022) were identified. Advanced preoperative testing was defined as prostate health index (PHI), prostate MRI, and/or negative preoperative biopsy. Descriptive statistics (Whitney-Mann U test, Chi-squared test) and multivariable logistic regression were performed. RESULTS: iPCa and icsPCa detection rates were 12.8% (104/811) and 4.4% (36/811), respectively. Advanced preoperative testing (406/811, 50%) was associated with younger age and higher (prostate specific antigen) PSA, prostate volume, and PSA density. On multivariable analysis, PHI ≥ 55 was associated with iPCa (OR 6.91, 95% CI 1.85-26.3, p = 0.004), and % free PSA (%fPSA) was associated with icsPCa (OR 0.83, 95% CI 0.67, 0.94, p = 0.01). GG1 disease comprised the majority of iPCa (65%, 68/104) with median 1% involvement. iPCa patients were followed with active surveillance (median follow up 9.3 months), with higher risk patients receiving prostate MRI and confirmatory biopsy. Three patients proceeded to radical prostatectomy or radiation. CONCLUSIONS: In the era of MRI and advanced biomarkers, the majority of iPCa following HoLEP is low volume GG1 suitable for active surveillance. A tentative follow-up strategy is proposed. Patients with PHI ≥ 55 or low %fPSA, even with negative prostate MRI, can consider preoperative prostate biopsy before HoLEP.
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Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.
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Complexo I de Transporte de Elétrons/genética , Osteossarcoma/genética , RNA Longo não Codificante/genética , RecQ Helicases/genética , Síndrome de Rothmund-Thomson/genética , Trifosfato de Adenosina/biossíntese , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Senescência Celular/genética , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação/genética , Osteoblastos/efeitos dos fármacos , Osteogênese/genética , Osteossarcoma/complicações , Osteossarcoma/patologia , Oxidiazóis/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Piperidinas/farmacologia , Síndrome de Rothmund-Thomson/complicações , Síndrome de Rothmund-Thomson/patologiaRESUMO
Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li-Fraumeni syndrome (LFS) patients, we investigate an oncogenic role of secreted frizzled-related protein 2 (SFRP2) in p53 mutation-associated OS development. Interestingly, we find that high SFRP2 expression in OS patient samples correlates with poor survival. Systems-level analyses identified that expression of SFRP2 increases during LFS OS development and can induce angiogenesis. Ectopic SFRP2 overexpression in normal osteoblast precursors is sufficient to suppress normal osteoblast differentiation and to promote OS phenotypes through induction of oncogenic molecules such as FOXM1 and CYR61 in a ß-catenin-independent manner. Conversely, inhibition of SFRP2, FOXM1, or CYR61 represses the tumorigenic potential. In summary, these findings demonstrate the oncogenic role of SFRP2 in the development of p53 mutation-associated OS and that inhibition of SFRP2 is a potential therapeutic strategy.
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Neoplasias Ósseas/genética , Carcinogênese/genética , Síndrome de Li-Fraumeni/patologia , Proteínas de Membrana/genética , Osteossarcoma/genética , Proteína Supressora de Tumor p53/genética , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proteína Rica em Cisteína 61/antagonistas & inibidores , Proteína Rica em Cisteína 61/genética , Proteína Forkhead Box M1/antagonistas & inibidores , Proteína Forkhead Box M1/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome de Li-Fraumeni/genética , Masculino , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Nus , Neovascularização Patológica/genética , Osteoblastos/citologia , Osteossarcoma/patologiaRESUMO
BACKGROUND: CDK11(p58), a Ser/Thr kinase that belongs to the cell division cycle 2-like 1 (CDC2L1) subfamily, is associated with cell cycle progression, tumorigenesis and apoptotic signaling. CDK11(p58) is also involved in the regulation of steroid receptors, such as androgen and estrogen receptors. We previously found that CDK11(p58) was abnormally expressed in prostate cancer. However, its role in breast cancer remains unclear. METHODS: CDK11(p58) expression was evaluated by immunohistochemical staining in a tissue array. A Transwell assay was used to detect invasion and metastasis in breast cancer cells. The TaqMan® Metastasis Gene Expression Assay was used to search for potential downstream factors in the CDK11(p58) signaling pathway. qRT-PCR was used to evaluate mRNA levels, and the dual luciferase array was used to analyze promoter activity. Western blotting was used to detect the protein level. RESULTS: CDK11(p58) expression was negatively correlated with node status (P = 0.012), relapse status (P = 0.002) and metastasis status (P = 0.023). Kaplan-Meier survival curves indicated that the disease-free survival (DFS) was significantly poor in breast cancer patients with low CDK11 expression. Interestingly, using the breast cancer cell lines ZR-75-30 and MDA-MB-231, we found that CDK11(p58) was capable of repressing the migration and invasion of ERα-positive breast cancer cells, but not ERα-negative breast cancer cells, in a kinase-dependent manner. Gene expression assays demonstrated that integrin ß3 mRNA was dramatically repressed by CDK11(p58), and luciferase results confirmed that the integrin ß3 promoter was inhibited by CDK11(p58) through ERα repression. The expression of integrin ß3 was highly related to ERα signaling; ERα overexpression stimulated integrin ß3 expression, whereas siRNA-mediated knockdown of ERα attenuated integrin ß3 expression. CONCLUSIONS: These data indicate that CDK11(p58) is an anti-metastatic gene in ERα-positive breast cancer and that the regulation of integrin ß3 by CDK11(p58) via the repression of ERα signaling may constitute part of a signaling pathway underlying breast cancer invasion.
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Neoplasias da Mama/patologia , Ciclina D3/genética , Ciclina D3/metabolismo , Receptor alfa de Estrogênio/metabolismo , Integrina beta3/genética , Transdução de Sinais , Adulto , Idoso , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Análise de SobrevidaRESUMO
INTRODUCTION: Renal cell neoplasms are known to be associated with paraneoplastic syndromes, and the association with Castleman-like regional lymphadenopathy has been rarely reported. We aim to characterize the association between renal neoplasms and Castleman-like lymphadenopathy. METHODS: A search for renal neoplasms with concurrent Castleman-like lymphadenopathy in one single medical institution from 2000 to 2023 resulted in 4 specimens. A literature search for "Castleman" and "renal neoplasm" resulted in 8 reports. Patients' demographics, clinical presentation, gross and histologic features, results of ancillary studies, treatment, and follow-up were evaluated. RESULTS: Our patients included 3 men and 1 woman, with a mean age of 60 years. Four different subtypes of renal neoplasms were diagnosed, including clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, and mucinous cystadenoma of the renal pelvis. For Castleman-like regional lymphadenopathy, 2 were plasma-cell predominant, and 2 were hyaline-vascular. After a median follow-up of 84 months, all patients were alive with no recurrence or progression of Castleman-like features following nephrectomies. CONCLUSION: Castleman-like regional lymphadenopathy should be considered in patients with renal tumors and lymphadenopathy. Although more prevalent in clear cell RCC, it can be also associated with other renal neoplasms. The concurrent lymphadenopathy was remitted following the renal tumor resections.
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BACKGROUND: To investigate the prognostic value of positive-to-negative changes in hormone receptor (HR) status after neoadjuvant chemotherapy (NCT) in patients with HR-positive breast cancer. METHODS: Data from 224 stage II-III breast cancer patients with positive HR status before NCT who had residual disease in the breast after NCT were collected. HR status of the residual tumors was retested after NCT. A survival analysis was performed in 214 patients with adjuvant endocrine therapy regardless of post-NCT HR status. The survival analysis also examined other clinical and pathologic variables. RESULTS: In total, 15.2 % of patients had a positive-to-negative change in HR status after NCT, and this change was observed more frequently in HER-2-positive tumors than HER-2-negative tumors (P = 0.001). In 214 patients who had been treated with adjuvant endocrine therapy regardless of post-NCT HR status, the alteration in HR status was an independent factor for the prediction of a poorer disease-free survival (P = 0.026) and overall survival (P < 0.001) in the adjuvant endocrine therapy patients. The 5-year disease-free survival and overall survival rates were 43.5 % and 59.8 %, respectively, in patients with HR status conversion and 67.8 % and 82.5 %, respectively, in patients whose HR status remained positive (log rank test P = 0.003 and P = 0.001). CONCLUSIONS: The switch of HR status after NCT is remarkable for HR-positive tumors. An HR-negative switch may identify patients who would benefit from alternative systemic therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Carboplatina/administração & dosagem , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Progesterona/efeitos dos fármacos , Taxoides/administração & dosagem , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , VinorelbinaRESUMO
OBJECTIVE: To investigate the clinicopathologic and immunohistochemical features as well as the differential diagnoses of the solid variant of mammary adenoid cystic carcinoma with basaloid features. METHODS: Clinical and pathological data were collected in four cases of the solid variant of mammary adenoid cystic carcinoma with basaloid features, and microscopic pathological examination and immunohistochemistry EnVision method were performed. The relevant literature was also reviewed. RESULTS: The four patients were female, with age ranged from 46 - 65 years old (average 56 years) and the maximum tumor diameter ranged from 1.5 to 2.5 cm. Microscopically, the tumors exhibited a predominantly solid architecture with a myxoid or hyalinized stroma. The tumor cells showed moderate to marked nuclear atypia, and a basaloid appearance with scanty cytoplasm and inconspicuous nucleoli, and ≥ 5 mitotic figures per 10 high power fields. Glandular space embedded within tumor islands could be noticed. These spaces were genuine glandular structures and the cells lining these true glandular lumens had more abundant and eosinophilic cytoplasm. Pseudoglandular spaces of cribriform pattern or variable shape were also occasionally seen, and these cysts contained homogenous eosinophilic material. Focal necrosis was found. All cases were negative for ER, PR and HER2. Immunohistochemical staining for CK5/6, CK7 and CK14 was positive in the genuine glandular structures. All cases were positive for CD10, but also positive with varying intensity from weak to strong for vimentin and CD117. Staining for Ki-67 in three patients showed 10% - 50% positive. CONCLUSIONS: The solid variant of mammary adenoid cystic carcinoma with basaloid features is a histologically distinctive and also a rare subset of the mammary adenoid cystic carcinoma. Awareness of its pathological features can help with the diagnosis as well as differential diagnosis. More cases are still needed for accurately assessing the prognosis of this particular tumor.
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Neoplasias da Mama/patologia , Carcinoma Adenoide Cístico/patologia , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/cirurgia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Carcinoma Basocelular/cirurgia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Queratina-14/metabolismo , Queratina-5/metabolismo , Queratina-7/metabolismo , Mastectomia/métodos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-kit/metabolismo , Vimentina/metabolismoRESUMO
As one of the most essential genome guardians, p53 and its mutants have been suggested associated with many types of cancers. Many p53 mutants function induce unique phenotypes, including carcinogenesis, metastasis, and drug resistance. The p53(R249S) mutation is the most prevalent and specific mutation associated with liver cancer development. Here, we demonstrate the generation of a heterozygous p53(R249S) mutation in the H9 human embryonic stem cell line using TALEN-mediated genome editing. The generated cell line maintains a normal karyotype, a pluripotent state and the in vivo capacity to develop a teratoma containing all three germ layer tissues.
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Técnicas de Cultura de Células/métodos , Edição de Genes , Células-Tronco Embrionárias Humanas/metabolismo , Mutação/genética , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Sequência de Bases , Linhagem Celular , Feminino , Heterozigoto , Humanos , CamundongosRESUMO
A multitude of signals are coordinated to maintain self-renewal in embryonic stem cells (ESCs). To unravel the essential internal and external signals required for sustaining the ESC state, we expand upon a set of ESC pluripotency-associated phosphoregulators (PRs) identified previously by short hairpin RNA (shRNA) screening. In addition to the previously described Aurka, we identify 4 additional PRs (Bub1b, Chek1, Ppm1g, and Ppp2r1b) whose depletion compromises self-renewal and leads to consequent differentiation. Global gene expression profiling and computational analyses reveal that knockdown of the 5 PRs leads to DNA damage/genome instability, activating p53 and culminating in ESC differentiation. Similarly, depletion of genome integrity-associated genes involved in DNA replication and checkpoint, mRNA processing, and Charcot-Marie-Tooth disease lead to compromise of ESC self-renewal via an increase in p53 activity. Our studies demonstrate an essential link between genomic integrity and developmental cell fate regulation in ESCs.
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Diferenciação Celular/genética , Células-Tronco Embrionárias/fisiologia , Instabilidade Genômica , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Linhagem Celular , Dano ao DNA , Perfilação da Expressão Gênica , Teste de Complementação Genética , Camundongos , Fosfoproteínas/genética , Fosfoproteínas/fisiologia , RNA Interferente Pequeno , Transdução de Sinais , Proteína Supressora de Tumor p53/fisiologiaRESUMO
Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease closely associated with epithelial-to-mesenchymal transition (EMT). This study aimed to investigate the role of EMT in metaplastic carcinoma. Methods: E-cadherin, Slug, Twist and Vimentin levels were detected by immunohistochemistry in 167 TNBC tumors, including 145 invasive carcinomas of no special type (ICONSTs), 14 spindle cell carcinomas (SpCCs) and 8 matrix-producing carcinomas (MPCs). Results: Nuclear Slug and Twist were more frequently detected in SpCC and MPC tumors than that in ICONST tumors (p<0.001). The rate of E-cadherin loss was much lower in the ICONST tumors than that in the SpCC and MPC tumors (p<0.001). Vimentin was expressed in all SpCC and MPC tumors. Furthermore, nuclear expression of Slug and Twist was positively associated with the cytoplasmic localization of Vimentin (p<0.001) and was inversely associated with membranous staining of E-cadherin (p<0.001). These trends were more apparent in the SpCC and MPC tumors than in the ICONST tumors. Follow-up data were available for 151 patients. The follow-up times ranged from 1 month to 11 years (mean: 74 m; median: 21 m). The median progression-free survival and overall survival times were 24 months (mean: 32 months) and 22 months (mean: 35 months), respectively. Tumor size, TNM stage and E-cadherin were found to be independent prognostic factors of TNBC. Conclusions: EMT may play an important role in TNBC, especially in MPC and SpCC. Further researches are needed to confirm this finding. The results of this study may facilitate the future development of targeted therapies based on alterations in the EMT and stem cell markers.
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Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer disorder. Patients with LFS are predisposed to a various type of tumors, including osteosarcoma--one of the most frequent primary non-hematologic malignancies in the childhood and adolescence. Therefore, LFS provides an ideal model to study this malignancy. Taking advantage of iPSC methodologies, LFS-associated osteosarcoma can be successfully modeled by differentiating LFS patient iPSCs to mesenchymal stem cells (MSCs), and then to osteoblasts--the cells of origin for osteosarcomas. These LFS osteoblasts recapitulate oncogenic properties of osteosarcoma, providing an attractive model system for delineating the pathogenesis of osteosarcoma. This manuscript demonstrates a protocol for the generation of iPSCs from LFS patient fibroblasts, differentiation of iPSCs to MSCs, differentiation of MSCs to osteoblasts, and in vivo tumorigenesis using LFS osteoblasts. This iPSC disease model can be extended to identify potential biomarkers or therapeutic targets for LFS-associated osteosarcoma.
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Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome de Li-Fraumeni/genética , Células-Tronco Mesenquimais/metabolismo , Osteossarcoma/diagnóstico , Adolescente , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Síndrome de Li-Fraumeni/metabolismo , Masculino , Osteossarcoma/patologiaRESUMO
The Retinoblastoma 1 (RB1) tumor suppressor, a member of the Retinoblastoma gene family, functions as a pocket protein for the functional binding of E2F transcription factors. About 1/3 of retinoblastoma patients harbor a germline RB1 mutation or deletion, leading to the development of retinoblastoma. Here, we demonstrate generation of a heterozygous deletion of the RB1 gene in the H1 human embryonic stem cell line using CRISPR/Cas9 nickase genome editing. The RB1 heterozygous knockout H1 cell line shows a normal karyotype, maintains a pluripotent state, and is capable of differentiation to the three germline layers.
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Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Técnicas de Cultura de Células/métodos , Desoxirribonuclease I/metabolismo , Deleção de Genes , Células-Tronco Embrionárias Humanas/citologia , Proteína do Retinoblastoma/genética , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Heterozigoto , Humanos , MasculinoRESUMO
The DNA helicase RECQL4 is known for its roles in DNA replication and repair. RECQL4 mutations cause several genetic disorders including Rothmund-Thomson syndrome (RTS), characterized by developmental defects and predisposition to osteosarcoma. Here we reprogrammed fibroblasts with a heterozygous RECQL4 mutation (c.1878â¯+â¯32_1878â¯+â¯55del24) to induced pluripotent stem cells (iPSCs). These iPSCs are pluripotent and are able to be differentiated into all three germ layers, providing a novel tool to further interrogate the role of RECQL4 DNA helicase in vitro.
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Células-Tronco Pluripotentes Induzidas/metabolismo , RecQ Helicases/genética , Adulto , Feminino , Heterozigoto , Humanos , Mutação , Adulto JovemRESUMO
The tumor suppressor gene TP53 is the most frequently mutated gene in human cancers. Many hot-spot mutations of TP53 confer novel functions not found in wild-type p53 and contribute to tumor development and progression. We report on the generation of a H1 human embryonic stem cell line carrying a homozygous TP53 R282W mutation using TALEN-mediated genome editing. The generated cell line demonstrates normal karyotype, maintains a pluripotent state, and is capable of generating a teratoma in vivo containing tissues from all three germ layers.
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Edição de Genes/métodos , Células-Tronco Embrionárias Humanas/metabolismo , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Homozigoto , Humanos , Masculino , Mutação/genética , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genéticaRESUMO
Genetic mutations in TP53 contribute to multiple human cancers. Here we report the generation of a H1-p53(R248W/R248W) human embryonic stem cell line harboring a homozygous TP53 R248W mutation created by TALEN-mediated precise gene editing. The H1-p53(R248W/R248W) cell line maintains a normal karyotype, robust pluripotency gene expression, and the potential to differentiate to the three germ layers.
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Edição de Genes , Homozigoto , Células-Tronco Embrionárias Humanas/metabolismo , Mutação , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição , Proteína Supressora de Tumor p53/genética , Linhagem Celular , Regulação da Expressão Gênica , Células-Tronco Embrionárias Humanas/citologia , Humanos , Masculino , Proteína Supressora de Tumor p53/metabolismoRESUMO
Li-Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germline mutations in TP53, the gene encoding p53, are responsible for most cases of LFS. TP53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered to be a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as to screen potential compounds targeting oncogenic p53. In this review we briefly summarize the biology of LFS and current understanding of the oncogenic functions of mutant p53 in cancer development. We discuss the strengths and limitations of current LFS disease models, and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS induced pluripotent stem cell (iPSC) platform to develop precision cancer therapy.
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Genes p53 , Síndrome de Li-Fraumeni/tratamento farmacológico , Síndrome de Li-Fraumeni/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Animais , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Mutação em Linhagem Germinativa , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/patologia , Síndrome de Li-Fraumeni/patologia , Neoplasias/patologia , Medicina de PrecisãoRESUMO
The elucidation of cancer pathogenesis has been hindered by limited access to patient samples, tumor heterogeneity and the lack of reliable model organisms. Characterized by their ability to self-renew indefinitely and differentiate into all cell lineages of an organism, pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide a powerful and unlimited source to generate differentiated cells that can be used to study disease biology, facilitate drug discovery and development, and provide key insights for developing personalized therapies. This article reviews the recent developments and technologies converting PSCs into clinically relevant model systems for cancer research.
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Modelos Biológicos , Neoplasias , Células-Tronco Pluripotentes , Animais , Diferenciação Celular , Humanos , OrganoidesRESUMO
The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances (AI) in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer driver genes (APC, KRAS, FBXW7, TCF7L2) and AIs in chromosomes 5, 7, and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis. Cancer Prev Res; 9(6); 417-27. ©2016 AACR.
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Adenoma/genética , Adenoma/patologia , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mucosa Intestinal/patologia , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Via de Sinalização Wnt/genéticaRESUMO
Invasive carcinoma of no special type (NST) with osteoclast-like giant cells (OGCs) represents a unique type of breast neoplasm, characterized by the presence of multinucleated OGCs and a vascularized, hemorrhagic stroma. Because of its rarity, the literature regarding this tumor remains limited and a detailed immunophenotype of this tumor has not been established as yet. We report a clinicopathological and immunohistochemical study of 42 patients with invasive carcinoma NST with OGCs. Macroscopically, these tumors presented as a well-delimited red-brown mass. A remarkable feature of the tumor was the presence of OGCs in the fibroblastic or hemorrhagic vascular stroma, as well as in the adjacent tumor nests or glandular lumina. The number of OGCs varied from 8 to 105 per 10 high-power fields with an average of 48. The tumors were well to moderately differentiated. Cribriform architecture was observed in 27 tumors (63 %). All of the 36 available tumors were of luminal phenotype, according to the Ki67 labeling index 89 % luminal A and 11 % luminal B. With a mean follow-up time of 46.4 months, lung metastasis was found in 2 patients (5 %) at 7 and 11 years after the operation, respectively. None of the other cases had presented with evidence of recurrence or metastasis. To the best of our knowledge, this is the largest reported series of invasive carcinoma NST with OGCs as yet. Our study revealed that invasive carcinoma NST with OGCs exhibit a luminal phenotype with luminal A subtype as the major group.
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Neoplasias da Mama/patologia , Carcinoma/patologia , Células Gigantes/patologia , Osteoclastos/patologia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Male breast carcinoma is a relatively rare disease. This study retrospectively investigated the clinicopathological features of 73 cases of male breast carcinoma in Chinese population, and classified the molecular subtype based on surrogate immunohistochemical definitions. The expression of GCDFP15, MGB, AR and FOXP1 were evaluated. Invasive carcinoma of no special type was the most common histological type in the study group (71.2%, 52/73). The luminal A and B subtypes were the major types of male breast carcinoma (60.9%, 34.8% respectively). AR and FOXP1 are expressed in 84.2% (48/57) and 71.9% (41/57) of the studied cases. Carcinoma of the luminal A subtype expressed GCDFP15 (73.5%, 25/34) and MGB (58.8%, 20/34) more frequently than cases of the luminal B subtypes (34.8%, 8/23 and 43.5%, 10/23, respectively; P = 0.004, P = 0.255, respectively). In conclusion, invasive carcinoma of no special type was the most common histological type in male breast carcinoma among Chinese population. Our study revealed that the luminal A and B subtypes were the major types of male breast carcinoma. AR and FOXP1 are highly expressed in male breast cancer. The luminal A subtype tends to express GCDFP15 and MGB more frequently than the luminal B subtype.