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1.
Anticancer Res ; 41(10): 4781-4787, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593427

RESUMO

BACKGROUND: Hypoxia can happen during solid tumor growth including osteosarcoma. This study investigated the relationship of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) on osteosarcoma cell growth and apoptosis under hypoxic conditions. MATERIALS AND METHODS: Human osteosarcoma cells were cultured under normal or hypoxic conditions. Inhibitors of HIF-1α and VEGF were applied to the cells separately or in combination to block the respective proteins. Cell proliferation and apoptosis were examined by MTT and TUNEL assays, and real-time PCR and ELISA were performed for mRNA and protein expression. RESULTS: There was a dramatic decrease of cell proliferation and an elevation of apoptosis under hypoxia. Blockage of HIF-1α and VEGFR enhanced the cell growth retardation and promoted apoptotic changes. Moreover, blockage of HIF-1α significantly eliminated the expression of VEGF in the cell culture media, and vice versa. CONCLUSION: HIF-1α and VEGF work closely in regulating osteosarcoma cell growth under hypoxic conditions and blockage of either of them may subsequently influence the presence of the other.


Assuntos
Apoptose , Proliferação de Células , Osteossarcoma/patologia , Hipóxia Tumoral , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Osteossarcoma/metabolismo , Hipóxia Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Nat Commun ; 12(1): 4413, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285210

RESUMO

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Feminino , Humanos , Mastectomia , Camundongos , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207825

RESUMO

Non-clear cell renal cell carcinomas are a miscellaneous group of tumors that include different histological subtypes, each one characterized by peculiarity in terms of genetic alteration, clinical behavior, prognosis, and treatment response. Because of their low incidence and poor enrollment in clinical trials, alongside their heterogeneity, additional efforts are required to better unveil the pathogenetic mechanisms and, consequently, to improve the treatment algorithm. Nowadays, tyrosine kinase inhibitors, mTOR and MET inhibitors, and even cisplatin-based chemotherapy and immunotherapy are potential weapons that are still under evaluation in this setting. Various biomarkers have been evaluated for detecting progression and monitoring renal cell carcinoma, but more studies are necessary to improve this field. In this review, we provide an overview on the molecular characteristics of this group of tumors and the recently published trials, giving an insight into what might become the future therapeutic standard in this complex world of non-clear cell kidney cancers.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met , Serina-Treonina Quinases TOR , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
4.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299136

RESUMO

Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an "immune hot" tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of "immune cold" tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed.


Assuntos
Biomarcadores Tumorais/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Terapia de Alvo Molecular , Sarcoma/imunologia , Microambiente Tumoral/imunologia , Animais , Biomarcadores Tumorais/imunologia , Humanos , Sarcoma/tratamento farmacológico , Sarcoma/patologia
5.
Methods Mol Biol ; 2324: 319-337, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34165724

RESUMO

Pseudogenes are commonly labeled as "junk DNA" given their perceived nonfunctional status. However, the advent of large-scale genomics projects prompted a revisit of pseudogene biology, highlighting their key functional and regulatory roles in numerous diseases, including cancers. Integrative analyses of cancer data have shown that pseudogenes can be transcribed and even translated, and that pseudogenic DNA, RNA, and proteins can interfere with the activity and function of key protein coding genes, acting as regulators of oncogenes and tumor suppressors. Capitalizing on the available clinical research, we are able to get an insight into the spread and variety of pseudogene biomarker and therapeutic potential. In this chapter, we describe pseudogenes that fulfill their role as diagnostic or prognostic biomarkers, both as unique elements and in collaboration with other genes or pseudogenes. We also report that the majority of prognostic pseudogenes are overexpressed and exert an oncogenic role in colorectal, liver, lung, and gastric cancers. Finally, we highlight a number of pseudogenes that can establish future therapeutic avenues.


Assuntos
Biomarcadores Tumorais/análise , Terapia de Alvo Molecular/métodos , Neoplasias/genética , Pseudogenes , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , DNA de Neoplasias/genética , Previsões , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Humanos , Neoplasias/tratamento farmacológico , Especificidade de Órgãos , Prognóstico , Transcrição Genética
6.
Commun Biol ; 4(1): 657, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079064

RESUMO

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.


Assuntos
Biomarcadores Tumorais/fisiologia , Claudinas/fisiologia , Neoplasias Colorretais/secundário , Neoplasias Hepáticas/patologia , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Adesão Celular/genética , Adesão Celular/fisiologia , Claudinas/antagonistas & inibidores , Claudinas/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Células HT29 , Hepatócitos/patologia , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos SCID , Domínios PDZ/genética , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Cancer Sci ; 112(9): 3520-3532, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34115916

RESUMO

Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (OXTR), which is a G-protein-coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of OXTR and its clinical relevance in MM. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and OXTR mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of OXTR and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, OXTR mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high OXTR expression showed poor overall survival. Moreover, OXTR knockdown dramatically decreased MM cell proliferation in cells with high OXTR expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. OXTR antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high OXTR expression, and oral administration of the OXTR antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that OXTR plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM.


Assuntos
Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/metabolismo , Piridinas/administração & dosagem , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Triazóis/administração & dosagem , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ocitocina/farmacologia , RNA Mensageiro/genética , Receptores de Ocitocina/genética , Transfecção , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064635

RESUMO

Ovarian cancer is a fatal gynecological malignancy. Although first-line chemotherapy and surgical operation are effective treatments for ovarian cancer, its clinical management remains a challenge owing to intrinsic or acquired drug resistance and relapse at local or distal lesions. Cancer stem cells (CSCs) are a small subpopulation of cells inside tumor tissues, and they can self-renew and differentiate. CSCs are responsible for the cancer malignancy involved in relapses as well as resistance to chemotherapy and radiation. These malignant properties of CSCs are regulated by cell surface receptors and intracellular pluripotency-associated factors triggered by internal or external stimuli from the tumor microenvironment. The malignancy of CSCs can be attenuated by individual or combined restraining of cell surface receptors and intracellular pluripotency-associated factors. Therefore, targeted therapy against CSCs is a feasible therapeutic tool against ovarian cancer. In this paper, we review the prominent roles of cell surface receptors and intracellular pluripotency-associated factors in mediating the stemness and malignancy of ovarian CSCs.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Microambiente Tumoral
9.
Cancer Treat Rev ; 98: 102225, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34082256

RESUMO

It is estimated that 604,127 patients were diagnosed with cervical cancer worldwide in 2020. While a small percentage of patients will have metastatic disease at diagnosis, a large percentage (15-61%) later develop advanced disease. For this cohort, treatment with systemic chemotherapy remains the standard of care, with a static 5-year survival rate over the last thirty years. Data on targetable molecular alterations in cervical cancer have lagged behind other more common tumor types thus stunting the development of targeted agents. In recent years, tumor genomic testing has been increasingly incorporated into our clinical practice, opening the door for a potential new era of personalized treatment for advanced cervical cancer. The interim results from the NCI-MATCH study reported an actionability rate of 28.4% for the cervical cancer cohort, suggesting a subset of patients may harbor mutations which that are targetable. This review sets out to summarize the key targeted agents currently under exploration either alone or in combination with existing treatments for cervical cancer.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Terapia de Alvo Molecular , Mutação , Medicina de Precisão , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Feminino , Humanos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/secundário
10.
Medicine (Baltimore) ; 100(25): e26388, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160418

RESUMO

ABSTRACT: Radioiodine-refractory thyroid cancers (IRTCs) are uncommon and have a poor prognosis. Treatment options for radioiodine-refractory and anaplastic tumors (ATCs) are limited. Although the genomic landscape of thyroid cancer has been studied, there is little evidence on whether next-generation sequencing (NGS) findings translate to tumor control.We analyzed all patients with IRTC and ATC who underwent commercially available NGS in 3 cancer centers.Twenty-two patients were identified, 16 patients with IRTCs and 6 patients with ATCs. Eighteen (82%) had targetable findings in NGS, nine patients were treated accordingly. Median progression-free survival for targeted treatment was 50 months [95% confidence interval (CI95%) 9.8-66.6] and2 months (CI95% 0.2-16.5) for IRTC and ATC, respectively. Of 4 patients who achieved durable responses of 7 to 50 months, 2 are ongoing. The estimated median OS of IRTC receiving targeted treatment was not reached (CI95% 89.7-111.4 months) and was 77.8 months (CI95% 52.5-114.6) for patients treated conventionally (P = .3).NGS may detect clinically significant genetic alterations and benefit patients with advanced thyroid cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Radioisótopos do Iodo/uso terapêutico , Recidiva Local de Neoplasia/terapia , Neoplasias da Glândula Tireoide/terapia , Adulto , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Radioisótopos do Iodo/farmacologia , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Estudos Retrospectivos , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/mortalidade
11.
Medicine (Baltimore) ; 100(19): e25773, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106609

RESUMO

RATIONALE: Anti-PD-1 antibody is the standard therapy for treatment-resistant gastric cancer, but only a limited number of patients respond. Additionally, cases of hyper-progressive disease (HPD) in which tumor growth accelerates after anti-PD-1 antibody administration have been reported; however, the biological mechanism has not been elucidated. PATIENT CONCERNS: In the present case, metastatic gastric cancer was treated with the anti-PD-1 antibody, nivolumab, as third-line treatment. DIAGNOSIS: After the initiation of nivolumab therapy, a rapidly enlarging para-aortic lymph nodes were observed leading to the diagnosis of HPD. INTERVENTIONS: Multiplex immunohistochemistry was used to examine immune cells infiltrating in the primary tumor and in liver metastasis which were obtained before nivolumab treatment, and in lymph node metastasis which presented with HPD after nivolumab therapy. OUTCOMES: In the primary tumor, helper T (Th) cells, cytotoxic T lymphocytes (CTLs), regulatory T (Treg) cells, and PD-L1-negative macrophages were observed. On the other hand, in metastatic lymph nodes presenting with HPD, PD-L1-positive macrophages prominently increased, while Treg cells, CTLs, and Th cells decreased. PD-L1 expression was not observed in gastric cancer cells among the three specimens. LESSONS: The findings suggest the possibility that PD-L1-positive M2 macrophage might contribute to acceleration of tumor growth with anti-PD-1 therapy in the present case.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Nivolumabe/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Progressão da Doença , Evolução Fatal , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
12.
Hematol Oncol ; 39 Suppl 1: 39-45, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105815

RESUMO

The treatment of classical Hodgkin lymphoma in young patients is one of the success stories of modern medicine. The use of risk- and response-adapted approaches to guide treatment decisions has led to impressive cure rates while reducing the long-term toxicity associated with more intensive therapies. Tissue biomarkers have not yet proven more effective than clinical characteristics for risk stratification of patients at presentation, but functional imaging features such as metabolic tumor volume may be used to predict response, if early observations can be validated. The success of treatment in younger patients has unfortunately not been mirrored in those over 60, where complex decision-making is often required, with a paucity of data from clinical trials. The use of PD1 blocking antibodies and brentuximab vedotin in this cohort, either alone or in combination with chemotherapy, may provide attractive options. The incorporation of frailty assessment, quality-of-life outcomes, and specialist geriatric input is also important to ensure the best outcomes for this diverse group.


Assuntos
Biomarcadores Tumorais , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Neoplasias , Medicina de Precisão , Receptor de Morte Celular Programada 1 , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo
13.
Biochem Pharmacol ; 188: 114589, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33932470

RESUMO

Circulating tumor cells (CTCs) play a crucial role in metastasis and became an emerging topic in today's cancer research. In addition, the analysis of CTCs in liquid biopsies will be a valuable tool for prognosis prediction and real time therapy monitoring. The characterization of CTCs may open up a new field of treatment strategy to prevent metastasis or maintain a stable disease. In 2013, the first cell cultures of CTCs have been established in vitro. Additionally, functional studies have been successfully performed over the last years. Meanwhile, more than 300 short-term CTC cultures and 42 long-term CTC cultures from a variety of tumor entities have been described. More than 45 inhibitors have already been tested for their efficacy to target CTCs in several studies in vitro as well as in xenograft mouse models in vivo. Here, we summarize the currently available data of these inhibition experiments and their effects in targeting CTCs. The results suggest that CTCs may be useful for individualized drug susceptibility testing.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Células Neoplásicas Circulantes/efeitos dos fármacos , Medicina de Precisão/métodos , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/tendências , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Células Neoplásicas Circulantes/metabolismo , Medicina de Precisão/tendências
14.
Biochem Biophys Res Commun ; 560: 172-178, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34000466

RESUMO

Aspirin can efficiently inhibit the glycolysis and proliferation of cancer cells, however, the underlying mechanism is poorly understood. Here, we report that aspirin attenuates the glycolysis and proliferation of hepatoma cells through modulating the levels of lysine 2-hydroxyisobutyrylation (Khib) of enolase 1 (ENO1). We found that aspirin decreased the levels of glucose consumption and lactate production in hepatoma cells. Moreover, 4 mM aspirin reduced the activities of ENO1, a key enzyme of glycolysis, and decreased the levels of ENO1 Khib in the cells. Interestingly, we identified that 4 mM aspirin could decrease the levels of Khib on many proteins by using pan Khib antibody in the cells. Interestingly, the activities of ENO1 could be rescued by the transient overexpression of ENO1, but not by ENO1 mutant (K281R). Moreover, we identified that the C646, an inhibitor of p300 which is a writer of Khib, could reduce the levels of ENO1 Khib, resulting in the decrease of ENO1 activities. The treatment with PDTC, an inhibitor of NF-κB which is a target of aspirin, could work well as C646 in the cells. Both of aspirin and C646 (or PDTC) displayed a stronger effect than the single treatment in the system. Functionally, ENO1, but not ENO1 mutant (K281R), could rescue the aspirin-induced inhibition of proliferation of liver cancer cells in vitro, suggesting that ENO1K281 is involved in the aspirin-mediated inhibition of liver cancer. Our finding provides new insights into the mechanism by which aspirin attenuates the glycolysis and proliferation of hepatoma cells.


Assuntos
Antineoplásicos/farmacologia , Aspirina/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Ligação a DNA/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Fosfopiruvato Hidratase/antagonistas & inibidores , Proteínas Supressoras de Tumor/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Aspirina/uso terapêutico , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Lisina/metabolismo , Fosfopiruvato Hidratase/química , Fosfopiruvato Hidratase/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo
15.
Medicine (Baltimore) ; 100(20): e25994, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011092

RESUMO

ABSTRACT: In precision oncology, immune check point blockade therapy has quickly emerged as novel strategy by its efficacy, where programmed death ligand 1 (PD-L1) expression is used as a clinically validated predictive biomarker of response for the therapy. Automating pathological image analysis and accelerating pathology evaluation is becoming an unmet need. Artificial Intelligence and deep learning tools in digital pathology have been studied in order to evaluate PD-L1 expression in PD-L1 immunohistochemistry image. We proposed a Dual-scale Categorization (DSC)-based deep learning method that employed 2 VGG16 neural networks, 1 network for 1 scale, to critically evaluate PD-L1 expression. The DSC-based deep learning method was tested in a cohort of 110 patients diagnosed as non-small cell lung cancer. This method showed a concordance of 88% with pathologist, which was higher than concordance of 83% of 1-scale categorization-based method. Our results show that the DSCbased method can empower the deep learning application in digital pathology and facilitate computer-aided diagnosis.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Diagnóstico por Computador/métodos , Neoplasias Pulmonares/diagnóstico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Aprendizado Profundo , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imuno-Histoquímica , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Seleção de Pacientes , Medicina de Precisão/métodos
16.
FASEB J ; 35(6): e21603, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33999448

RESUMO

Extracellular matrix (ECM) plays an important role in the progression of cancer. Collagen is the most abundant component in ECM, and it is involved in the biological formation of cancer. Although type XI collagen is a minor fibrillar collagen, collagen XI alpha 1 chain (COL11A1) has been found to be upregulated in a variety of cancers including ovarian cancer, breast cancer, thyroid cancer, pancreatic cancer, non-small-cell lung cancer, and transitional cell carcinoma of the bladder. High levels of COL11A1 usually predict poor prognosis, while COL11A1 is related to angiogenesis, invasion, and drug resistance of cancer. However, little is known about the specific mechanism by which COL11A1 regulates tumor progression. Here, we have organized and summarized the recent developments regarding elucidation of the relationship between COL11A1 and various cancers, as well as the interaction between COL11A1 and intracellular signaling pathways. In addition, we have selected therapeutic agents targeting COL11A1. All these indicate the possibility of using COL11A1 as a target for cancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Colágeno Tipo XI/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
17.
Eur J Pharmacol ; 902: 174119, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33930385

RESUMO

MUC1 seems to be promising target in cancer cells due to its abundant and specifically altered expression as well as differential distribution pattern relative to normal tissues. Rosmarinic acid (RA) is a natural, polyphenolic compound with pharmacological activities, including anti-cancer. Herein, we aim to explore the effect of combined action of anti-MUC1 and RA on selected cancer-related factors in AGS gastric cancer cells. Cancer cells were treated with 100, 200 µM rosmarinic acid, 5 µg/ml anti-MUC1 and acid together with antibody. Western blotting, ELISA and RT-PCR were used to assess the expression of MUC1, selected sugar antigens, enzymes participating in protein glycosylation, Gal-3, p53, pro- and anti-apoptotic factors, and caspases-3,-8,-9 in cancer cells. MUC1 mRNA was significantly suppressed by combined action of anti-MUC1 and RA. Such treatment markedly inhibited expression of cancer-related Tn, T, sialyl Tn, sialyl T, and fucosylated sugar antigens as well as mRNA expression of enzymes participating in their formation: ppGalNAcT2, C1GalT1, ST6GalNAcT2, ST3GalT1 and FUT4. C1GalT1 was suppressed also on protein level. Gal-3, factor likely participating in metastasis, was significantly suppressed on mRNA level by RA administrated with anti-MUC1. Pro-apoptotic Bax protein and Bad mRNA were significantly induced, and anti-apoptotic Bcl-2 mRNA expression was inhibited by such treatment. Combined action of mAb and RA markedly increased caspase-9 mRNA expression. Results of the study indicate that combined action of anti-MUC1 and RA is more effective than monotherapy in relation to examined cancer related factors. Such treatment can be considered as new, promising strategy in gastric cancer therapy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antineoplásicos/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Mucina-1/imunologia , Mucina-1/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Galectinas/genética , Galectinas/metabolismo , Glicosilação/efeitos dos fármacos , Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Humanos , Mucina-1/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
18.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33914706

RESUMO

Melanoma dedifferentiation has been reported to be a state of cellular resistance to targeted therapies and immunotherapies as cancer cells revert to a more primitive cellular phenotype. Here, we show that, counterintuitively, the biopsies of patient tumors that responded to anti-programmed cell death 1 (anti-PD-1) therapy had decreased expression of melanocytic markers and increased neural crest markers, suggesting treatment-induced dedifferentiation. When modeling the effects in vitro, we documented that melanoma cell lines that were originally differentiated underwent a process of neural crest dedifferentiation when continuously exposed to IFN-γ, through global chromatin landscape changes that led to enrichment in specific hyperaccessible chromatin regions. The IFN-γ-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype.


Assuntos
Biomarcadores Tumorais , Desdiferenciação Celular/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Interferon gama/metabolismo , Melanoma , Proteínas de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo
19.
Nat Rev Clin Oncol ; 18(8): 473-487, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33790428

RESUMO

Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.


Assuntos
Adenocarcinoma/terapia , Biomarcadores Tumorais/fisiologia , Neoplasias Esofágicas/terapia , Terapia de Alvo Molecular , Neoplasias Gástricas/terapia , Adenocarcinoma/patologia , Biomarcadores Farmacológicos/análise , Biomarcadores Tumorais/antagonistas & inibidores , Progressão da Doença , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Estadiamento de Neoplasias , Neoplasias Gástricas/patologia , Terapias em Estudo/métodos , Terapias em Estudo/tendências
20.
Nat Immunol ; 22(5): 595-606, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33903766

RESUMO

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.


Assuntos
Biomarcadores Tumorais/metabolismo , Heme Oxigenase-1/metabolismo , Neoplasias Pulmonares/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/imunologia , Feminino , Heme/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/sangue , Heme Oxigenase-1/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Melanoma/mortalidade , Melanoma/secundário , Melanoma/terapia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Células Progenitoras Mieloides/imunologia , Células Progenitoras Mieloides/metabolismo , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/metabolismo
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