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1.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200503

RESUMO

The interaction of tumor cells with blood vessels is one of the key steps during cancer metastasis. Metastatic cancer cells exhibit phenotypic state changes during this interaction: (1) they form tunneling nanotubes (TNTs) with endothelial cells, which act as a conduit for intercellular communication; and (2) metastatic cancer cells change in order to acquire an elongated phenotype, instead of the classical cellular aggregates or mammosphere-like structures, which it forms in three-dimensional cultures. Here, we demonstrate mechanistically that a siRNA-based knockdown of the exocyst complex protein Sec3 inhibits TNT formation. Furthermore, a set of pharmacological inhibitors for Rho GTPase-exocyst complex-mediated cytoskeletal remodeling is introduced, which inhibits TNT formation, and induces the reversal of the more invasive phenotype of cancer cell (spindle-like) into a less invasive phenotype (cellular aggregates or mammosphere). Our results offer mechanistic insights into this nanoscale communication and shift of phenotypic state during cancer-endothelial interactions.


Assuntos
Neoplasias da Mama/patologia , Comunicação Celular , Endotélio Vascular/patologia , Nanotubos/química , Proteínas de Transporte Vesicular/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Técnicas de Cultura de Células , Citoplasma/metabolismo , Citoesqueleto/metabolismo , Feminino , Humanos , Metástase Neoplásica , Fenótipo , Células Tumorais Cultivadas , Proteínas de Transporte Vesicular/genética , Proteínas rho de Ligação ao GTP/genética
2.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202777

RESUMO

Long noncoding RNAs (lncRNAs) have been identified as contributors to the development and progression of cancer through various functions and mechanisms. LncRNA GAS5 is downregulated in multiple cancers and acts as a tumor suppressor in breast cancer. GAS5 interacts with various proteins (e.g., E2F1, EZH2, and YAP), DNA (e.g., the insulin receptor promoter), and various microRNAs (miRNAs). In breast cancer, GAS5 binds with miR-21, miR-222, miR-221-3p, miR-196a-5p, and miR-378a-5p that indicates the presence of several elements for miRNA binding (MREs) in GAS5. Mediated by the listed miRNAs, GAS5 is involved in the upregulation of a number of mRNAs of suppressor proteins such as PTEN, PDCD4, DKK2, FOXO1, and SUFU. Furthermore, the aberrant promoter methylation is involved in the regulation of GAS5 gene expression in triple-negative breast cancer and some other carcinomas. GAS5 can stimulate apoptosis in breast cancer via diverse pathways, including cell death receptors and mitochondrial signaling pathways. GAS5 is also a key player in the regulation of some crucial signal pathways in breast cancer, such as PI3K/AKT/mTOR, Wnt/ß-catenin, and NF-κB signaling. Through epigenetic and other mechanisms, GAS5 can increase sensitivity to multiple drugs and improve prognosis. GAS5 is thus a promising target in the treatment of breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Animais , Apoptose/genética , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Metilação de DNA , Epigênese Genética , Feminino , Humanos , MicroRNAs/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais
3.
Medicine (Baltimore) ; 100(27): e26619, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232220

RESUMO

ABSTRACT: The incidence of primary metastatic breast cancer (PMBC) has not decreased despite the increasing popularity of mammography screening and data on the survival among these patients are limited. Therefore, we conducted an extensive population-based study to investigate the factors influencing the survival of patients with PMBC.We identified 14,306 patients with de novo stage-IV breast cancer using the Surveillance, Epidemiology, and End Results data from 2010 to 2015. The overall survival (OS) time and breast cancer-specific survival (BCSS) time were compared by the Kaplan-Meier method. Univariate and multivariate analyses were performed to determine the effect of different prognostic factors.Patients with hormone receptor positive/human epidermal growth factor receptor 2 positive showed the longest median survival time in OS (39 months) and BCSS (43 months), and those with triple negative exhibited the shortest in OS (11 months) and BCSS (12 months). We concluded that patients who had undergone primary tumor surgery had better survival than those who did not. The incidence of distant visceral metastasis in the whole cohort was as follows: bone, lung, liver, and brain. This study also substantiated that patients with only brain metastasis had poorer survival than patients with metastasis at multiple sites metastasis, not including brain metastasis (P < .0001).This study confirmed that molecular subtypes, metastatic site and primary tumor surgery were associated with the survival of PMBC patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/cirurgia , Mastectomia/métodos , Programa de SEER , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/secundário , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos
4.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(3): 445-451, 2021 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-34238422

RESUMO

Breast cancer patients with bone,liver and lung metastases tend to have a poor prognosis.According to Paget's "seed and soil" theory,metastatic cancer cell "seeds" must fall on congenial target organ "soil".Studies have shown that myeloid-derived suppressor cells(MDSCs)can be recruited at the site of breast cancer metastasis in advance and play a role in the metastasis of breast cancer cells.This paper reviews the biological characteristics of MDSCs,the roles of MDSCs in peripheral circulation,prometastatic niche,and metastatic site during breast cancer metastasis,as well as the research progress of MDSCs-targeted treatment of breast cancer metastasis.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Células Supressoras Mieloides , Feminino , Humanos , Metástase Neoplásica , Microambiente Tumoral
5.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199298

RESUMO

BACKGROUND: Preclinical drug development studies rarely consider the impact of a candidate drug on established metastatic disease. This may explain why agents that are successful in subcutaneous and even orthotopic preclinical models often fail to demonstrate efficacy in clinical trials. It is reasonable to anticipate that sites of metastasis will be phenotypically unique, as each tumor will have evolved heterogeneously with respect to gene expression as well as the associated phenotypic outcome of that expression. The objective for the studies described here was to gain an understanding of the tumor heterogeneity that exists in established metastatic disease and use this information to define a preclinical model that is more predictive of treatment outcome when testing novel drug candidates clinically. METHODS: Female NCr nude mice were inoculated with fluorescent (mKate), Her2/neu-positive human breast cancer cells (JIMT-mKate), either in the mammary fat pad (orthotopic; OT) to replicate a primary tumor, or directly into the left ventricle (intracardiac; IC), where cells eventually localize in multiple sites to create a model of established metastasis. Tumor development was monitored by in vivo fluorescence imaging (IVFI). Subsequently, animals were sacrificed, and tumor tissues were isolated and imaged ex vivo. Tumors within organ tissues were further analyzed via multiplex immunohistochemistry (mIHC) for Her2/neu expression, blood vessels (CD31), as well as a nuclear marker (Hoechst) and fluorescence (mKate) expressed by the tumor cells. RESULTS: Following IC injection, JIMT-1mKate cells consistently formed tumors in the lung, liver, brain, kidney, ovaries, and adrenal glands. Disseminated tumors were highly variable when assessing vessel density (CD31) and tumor marker expression (mkate, Her2/neu). Interestingly, tumors which developed within an organ did not adopt a vessel microarchitecture that mimicked the organ where growth occurred, nor did the vessel microarchitecture appear comparable to the primary tumor. Rather, metastatic lesions showed considerable variability, suggesting that each secondary tumor is a distinct disease entity from a microenvironmental perspective. CONCLUSIONS: The data indicate that more phenotypic heterogeneity in the tumor microenvironment exists in models of metastatic disease than has been previously appreciated, and this heterogeneity may better reflect the metastatic cancer in patients typically enrolled in early-stage Phase I/II clinical trials. Similar to the suggestion of others in the past, the use of models of established metastasis preclinically should be required as part of the anticancer drug candidate development process, and this may be particularly important for targeted therapeutics and/or nanotherapeutics.


Assuntos
Biomarcadores Tumorais/metabolismo , Microambiente Tumoral , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Pulmão/patologia , Camundongos Nus , Metástase Neoplásica
6.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203721

RESUMO

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.


Assuntos
Metástase Neoplásica/tratamento farmacológico , Extratos Vegetais/farmacologia , Vitis/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Quimiocinas/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/metabolismo , Sementes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
7.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205118

RESUMO

During metastasis, cancer cells that originate from the primary tumor circulate in the bloodstream, extravasate, and form micrometastases at distant locations. Several lines of evidence suggest that specific interactions between cancer cells and endothelial cells, in particular tumor cell adhesion to the endothelium and transendothelial migration, play a crucial role in extravasation. Here we have studied the role of vascular endothelial (VE)-cadherin which is expressed aberrantly by breast cancer cells and might promote such interactions. By comparing different human breast cancer cell lines, we observed that the number of cancer cells that adhered to endothelium correlated with VE-cadherin expression levels. VE-cadherin silencing experiments confirmed that VE-cadherin enhances cancer cell adhesion to endothelial cells. However, in contrast, the number of cancer cells that incorporated into the endothelium was not dependent on VE-cadherin. Thus, it appears that cancer cell adhesion and incorporation are distinct processes that are governed by different molecular mechanisms. When cancer cells incorporated into the endothelial monolayer, they formed VE-cadherin positive contacts with endothelial cells. On the other hand, we also observed tumor cells that had displaced endothelial cells, reflecting either different modes of incorporation, or a temporal sequence where cancer cells first form contact with endothelial cells and then displace them to facilitate transmigration. Taken together, these results show that VE-cadherin promotes the adhesion of breast cancer cells to the endothelium and is involved in the initial phase of incorporation, but not their transmigration. Thus, VE-cadherin might be of relevance for therapeutic strategies aiming at preventing the metastatic spread of breast cancer cells.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Caderinas/genética , Adesão Celular/genética , Endotélio Vascular/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Cocultura , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Imagem Molecular/métodos , Metástase Neoplásica
8.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206143

RESUMO

Primary liver cancer accounts for the third most deadly type of malignant tumor globally, and approximately 80% of the cases are hepatocellular carcinoma (HCC), which highly relies on the activity of hypoxia responsive pathways to bolster its metastatic behaviors. MicroRNA-29a (MIR29A) has been shown to exert a hepatoprotective effect on hepatocellular damage and liver fibrosis induced by cholestasis and diet stress, while its clinical and biological role on the activity hypoxia responsive genes including LOX, LOXL2, and VEGFA remains unclear. TCGA datasets were retrieved to confirm the differential expression and prognostic significance of all genes in the HCC and normal tissue. The Gene Expression Omnibus (GEO) dataset was used to corroborate the differential expression and diagnostic value of MIR29A. The bioinformatic identification were conducted to examine the interaction of MIR29A with LOX, LOXL2, and VEGFA. The suppressive activity of MIR29A on LOX, LOXL2, and VEGF was verified by qPCR, immunoblotting, and luciferase. The effect of overexpression of MIR29A-3p mimics in vitro on apoptosis markers (caspase-9, -3, and poly (ADP-ribose) polymerase (PARP)); cell viability and wound healing performance were examined using immunoblot and a WST-1 assay and a wound healing assay, respectively. The HCC tissue presented low expression of MIR29A, yet high expression of LOX, LOXL2, and VEGFA as compared to normal control. Serum MIR29A of HCC patients showed decreased levels as compared to that of normal control, with an area under curve (AUC) of 0.751 of a receiver operating characteristic (ROC) curve. Low expression of MIR29A and high expression of LOX, LOXL2, and VEGFA indicated poor overall survival (OS). MIR29A-3p was shown to target the 3'UTR of LOX, LOXL2, and VEGFA. Overexpression of MIR29A-3p mimic in HepG2 cells led to downregulated gene and protein expression levels of LOX, LOXL2, and VEGFA, wherein luciferase reporter assay confirmed that MIR29A-3p exerts the inhibitory activity via directly binding to the 3'UTR of LOX and VEGFA. Furthermore, overexpression of MIR29A-3p mimic induced the activity of caspase-9 and -3 and PARP, while it inhibited the cell viability and wound healing performance. Collectively, this study provides novel insight into a clinical-applicable panel consisting of MIR29, LOX, LOXL2, and VEGFA and demonstrates an anti-HCC effect of MIR29A via comprehensively suppressing the expression of LOX, LOXL2, and VEGFA, paving the way to a prospective theragnostic approach for HCC.


Assuntos
Aminoácido Oxirredutases/genética , Carcinoma Hepatocelular/genética , MicroRNAs/genética , Proteína-Lisina 6-Oxidase/genética , Fator A de Crescimento do Endotélio Vascular/genética , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Transdução de Sinais/genética
9.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207286

RESUMO

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's "Seed and Soil" hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor ß (TGFß), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.


Assuntos
Neoplasias/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Animais , Diferenciação Celular , Humanos , Imunoterapia/métodos , Metástase Neoplásica , Neoplasias/imunologia , Neoplasias/terapia , Macrófagos Associados a Tumor/patologia
10.
Urol Clin North Am ; 48(3): 349-363, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34210490

RESUMO

Recent studies show that the prevalence of germline pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes in metastatic prostate cancer is higher than previously recognized and higher than in unaffected men. Specific gene dysfunction is important in prostate cancer initiation and/or evolution to metastases. This article reviews key literature on individual genes, recognizing BRCA2 as the gene most commonly altered in the metastatic setting. This article discusses the importance of representative and diverse inclusion, and efforts to advance management for at-risk carrier populations to maximize clinical benefit.


Assuntos
Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Antineoplásicos/uso terapêutico , Dano ao DNA , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Indóis/uso terapêutico , Masculino , Metástase Neoplásica/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico
11.
Urol Clin North Am ; 48(3): 365-371, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34210491

RESUMO

Germline testing should be performed to support treatment selection for patients with metastatic prostate cancer, and should be identified in patients with high-risk localized disease. Patients with germline BRCA1/2 mutations should be educated regarding additional personal cancer risk, and risk for family members. Guidelines recommend that all men with metastatic prostate cancer should also undergo somatic tissue and germline testing for priority genes BRCA1/2, PALB2, ATM, and MSH2/6. The advent of high throughput sequencing enables patients to be tested for a more comprehensive panel of germline and somatic mutations.


Assuntos
Predisposição Genética para Doença , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Dano ao DNA , Reparo do DNA , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Indóis/uso terapêutico , Masculino , Metástase Neoplásica/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico
12.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207660

RESUMO

Caseinolytic protease P (ClpP) is a mitochondrial serine protease. In mammalian cells, the heterodimerization of ClpP and its AAA+ ClpX chaperone results in a complex called ClpXP, which has a relevant role in protein homeostasis and in maintaining mitochondrial functionality through the degradation of mitochondrial misfolded or damaged proteins. Recent studies demonstrate that ClpP is upregulated in primary and metastatic human tumors, supports tumor cell proliferation, and its overexpression desensitizes cells to cisplatin. Interestingly, small modulators of ClpP activity, both activators and inhibitors, are able to impair oxidative phosphorylation in cancer cells and to induce apoptosis. This review provides an overview of the role of ClpP in regulating mitochondrial functionality, in supporting tumor cell proliferation and cisplatin resistance; finally, we discuss whether this protease could represent a new prognostic marker and therapeutic target for the treatment of cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Endopeptidase Clp/metabolismo , Mitocôndrias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Proliferação de Células/genética , Endopeptidase Clp/genética , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia
13.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207035

RESUMO

Breast cancer is the most commonly occurring cancer in women of Western countries and is the leading cause of cancer-related mortality. The breast tumor microenvironment contains immune cells, fibroblasts, adipocytes, mesenchymal stem cells, and extracellular matrix. Among these cells, macrophages or tumor-associated macrophages (TAMs) are the major components of the breast cancer microenvironment. TAMs facilitate metastasis of the breast tumor and are responsible for poor clinical outcomes. High TAM density was also found liable for the poor prognosis of breast cancer. These observations make altering TAM function a potential therapeutic target to treat breast cancer. The present review summarizes the origin of TAMs, mechanisms of macrophage recruitment and polarization in the tumor, and the contributions of TAMs in tumor progression. We have also discussed our current knowledge about TAM-targeted therapies and the roles of miRNAs and exosomes in re-educating TAM function.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Comunicação Celular , Progressão da Doença , Suscetibilidade a Doenças , Exossomos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Imunomodulação , Ativação de Macrófagos/imunologia , MicroRNAs/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Carga Tumoral , Macrófagos Associados a Tumor/patologia
14.
J Radiol Case Rep ; 15(4): 7-16, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34276871

RESUMO

Extraskeletal osteosarcoma is a highly aggressive malignant osteoid forming mesenchymal neoplasm arising from soft tissues which accounts for 1% of all soft tissue sarcomas. We report the case of a 46-year-old female with no significant past medical history presenting to an emergency department with a right lateral thigh mass following minor trauma. She was eventually found to have high grade extraskeletal osteosarcoma with rapid progression of disease resulting in patient demise. Differentiation of these lesions from alternative processes relies on specific imaging and pathologic features. Differential diagnoses include both benign and malignant etiologies such as myositis ossificans, soft tissue hemangiomas, and other malignant soft tissue neoplasms such as epithelial and synovial sarcoma.


Assuntos
Osteossarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Osteossarcoma/diagnóstico por imagem , Neoplasias de Tecidos Moles/diagnóstico por imagem
15.
Nat Commun ; 12(1): 4091, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215748

RESUMO

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Heterogeneidade Genética , Evasão da Resposta Imune , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Células Neoplásicas Circulantes/imunologia , Idoso , Animais , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Quimiocina CCL5/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Metástase Neoplásica , Células Neoplásicas Circulantes/metabolismo , Prognóstico , RNA-Seq , Transcriptoma , Microambiente Tumoral
16.
Clin Ter ; 172(4): 260-263, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34247206

RESUMO

Abstract: Nasopharyngeal carcinoma, one of the most common head and neck cancers in Southeast Asia, is uncommon in Western countries and it is frequently diagnosed in advanced stage. Chemotherapy given with radiation therapy, followed by more chemotherapy, is the standard of care of stage IV nasopharyngeal carcinoma but Cetuximab, an epidermal growth factor (EGFR) inhibitor, is now making its way in the treatment of locoregionally advanced nasopharyngeal carcinoma. We report a case of 58 years old patient with metastatic nasopharyngeal carcinoma with an astonishing response to Cetuximab. At the time of writing, the patient is still in treatment with Cetuximab with excellent disease control.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Cisplatino/uso terapêutico , Fluoruracila/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Nat Commun ; 12(1): 4299, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262038

RESUMO

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO3-assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Nanomedicina/métodos , Neoplasias/terapia , Ablação por Radiofrequência , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Carbonato de Cálcio/química , Carbonato de Cálcio/uso terapêutico , Catálise , Linhagem Celular Tumoral , Terapia Combinada , Ferroptose/efeitos dos fármacos , Hemina/química , Hemina/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/química , Lipoxigenase/uso terapêutico , Camundongos , Metástase Neoplásica , Neoplasia Residual , Neoplasias/imunologia , Neoplasias/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/uso terapêutico , Coelhos
18.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209703

RESUMO

The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis. The tumor microenvironment (TME) can influence macrophage recruitment and polarization, giving way to these pro-tumorigenic outcomes. Investigating TME-induced macrophage polarization is critical for further understanding of TAM-related pro-tumor outcomes and potential development of new therapeutic approaches. This review explores the current understanding of TME-induced macrophage polarization and the role of M2-polarized macrophages in promoting tumor progression.


Assuntos
Ativação de Macrófagos/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Citocinas/metabolismo , Humanos , Hipóxia/genética , Hipóxia/imunologia , Hipóxia/metabolismo , Imunofenotipagem , Inflamação/etiologia , Inflamação/metabolismo , Ativação de Macrófagos/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Transdução de Sinais , Macrófagos Associados a Tumor/patologia
19.
Breast Cancer Res Treat ; 189(1): 63-80, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34216317

RESUMO

BACKGROUND: Cancer-associated fibroblasts (CAFs) are recruited to the tumor microenvironment (TME) and are critical drivers of breast cancer (BC) malignancy. Circulating tumor cells (CTCs) travel through hematogenous routes to establish metastases. CTCs circulate both individually and, more rarely, in clusters with other cell types. Clusters of CTCs have higher metastatic potential than single CTCs. Previously, we identified circulating CAFs (cCAFs) in patients with BC and found that while healthy donors had no CTCs or cCAFs, both were present in most Stage IV patients. cCAFs circulate individually, as cCAF-cCAF homotypic clusters, and in heterotypic clusters with CTCs. METHODS: In this study, we evaluate CTCs, cCAFs, and heterotypic cCAF-CTC clusters in patients with stage I-IV BC. We evaluate the association of heterotypic clusters with BC disease progression and metastasis in a spontaneous mouse model. Using previously established primary BC and CAF cell lines, we examine the metastatic propensity of heterotypic cCAF-CTC clusters in orthotopic and tail vein xenograft mouse models of BC. Using an in vitro clustering assay, we determine factors that may be involved in clustering between CAF and BC cells. RESULTS: We report that the dissemination of CTCs, cCAFs, and clusters is an early event in BC progression, and we find these clusters in all clinical stages of BC. Furthermore, cCAFs-CTC heterotypic clusters have a higher metastatic potential than homotypic CTC clusters in vivo. We also demonstrate that the adhesion and stemness marker CD44, found on a subset of CTCs and CAF cells, is  involved in heterotypic clustering of these cells. CONCLUSION: We identify a novel subset of circulating tumor cell clusters that are enriched with stromal CAF cells in BC patient blood and preclinical mouse models of BC metastasis. Our data suggest that clustering of CTCs with cCAFs augments their metastatic potential and that CD44 might be an important mediator of heterotypic clustering of cCAFs and BC cells.


Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Células Neoplásicas Circulantes , Animais , Biomarcadores Tumorais , Fibroblastos Associados a Câncer/patologia , Contagem de Células , Análise por Conglomerados , Feminino , Humanos , Camundongos , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Microambiente Tumoral
20.
Nat Commun ; 12(1): 4308, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262028

RESUMO

Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.


Assuntos
Neoplasias da Mama/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-11/metabolismo , Fator de Transcrição MafF/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Hipóxia Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator de Transcrição MafF/genética , Camundongos , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Proteínas Nucleares/genética , Prognóstico , Transdução de Sinais , Transcrição Genética
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