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Oncogene ; 39(5): 987-1003, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31591478


Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates the cell differentiation-related gene expression profile by suppressing Wnt pathway activity and reducing mesenchymal traits and survival of CR-CSCs. Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect and sensitizes tumor cells to standard chemotherapy regardless of the mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations were affected to a lower extent by the combination of BMP7v and chemotherapy. However, the addition of a PI3K inhibitor to the BMP7v-based combination potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion size. These data suggest that BMP7v treatment may represent a useful antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to both standard and targeted therapies.

Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/farmacologia , Neoplasias Colorretais/patologia , Mutação , Animais , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Humanos , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
Epigenomics ; 11(6): 587-604, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066579


Aim: To investigate the genome-wide methylation of genetically characterized colorectal cancer stem cell (CR-CSC) lines. Materials & methods: Eight CR-CSC lines were isolated from primary colorectal cancer (CRC) tissues, cultured and characterized for aneuploidy, mutational status of CRC-related genes and microsatellite instability (MSI). Genome-wide DNA methylation was assessed by MethylationEPIC microarray. Results: We describe a distinctive methylation pattern that is maintained following in vivo passages in immune-compromised mice. We identified an epigenetic CR-CSC signature associated with MSI. We noticed that the preponderance of the differentially methylated positions do not reside at CpG islands, but spread to shelf and open sea regions. Conclusion: Given that CRCs with MSI-high status have a lower metastatic potential, the identification of a MSI-related methylation signature could provide new insights and possible targets into metastatic CRC.

Neoplasias do Colo/genética , Metilação de DNA , Instabilidade de Microssatélites , Células-Tronco Neoplásicas/patologia , Animais , Neoplasias do Colo/patologia , Ilhas de CpG/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Xenoenxertos , Humanos , Camundongos
BMC Cancer ; 18(1): 1176, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30482160


BACKGROUND: It has been proposed that mesenchymal stromal cells (MSCs) promote tumor progression by interacting with tumor cells and other stroma cells in the complex network of the tumor microenvironment. We characterized MSCs isolated and expanded from tumor tissues of pediatric patients diagnosed with neuroblastomas (NB-MSCs) to define interactions with the tumor microenvironment. METHODS: Specimens were obtained from 7 pediatric patients diagnosed with neuroblastoma (NB). Morphology, immunophenotype, differentiation capacity, proliferative growth, expression of stemness and neural differentiation markers were evaluated. Moreover, the ability of cells to modulate the immune response, i.e. inhibition of phytohemagglutinin (PHA) activated peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cytotoxic function, was examined. Gene expression profiles, known to be related to tumor cell stemness, Wnt pathway activation, epithelial-mesenchymal transition (EMT) and tumor metastasis were also evaluated. Healthy donor bone marrow-derived MSCs (BM-MSC) were employed as controls. RESULTS: NB-MSCs presented the typical MSC morphology and phenotype. They showed a proliferative capacity superimposable to BM-MSCs. Stemness marker expression (Sox2, Nanog, Oct3/4) was comparable to BM-MSCs. NB-MSC in vitro osteogenic and chondrogenic differentiation was similar to BM-MSCs, but NB-MSCs lacked adipogenic differentiation capacity. NB-MSCs reached senescence phases at a median passage of P7 (range, P5-P13). NB-MSCs exhibited greater immunosuppressive capacity on activated T lymphocytes at a 1:2 (MSC: PBMC) ratio compared with BM-MSCs (p = 0.018). NK cytotoxic activity was not influenced by co-culture, either with BM-MSCs or NB-MSCs. Flow-cytometry cell cycle analysis showed that NB-MSCs had an increased number of cells in the G0-G1 phase compared to BM-MSCs. Transcriptomic profiling results indicated that NB-MSCs were enriched with EMT genes compared to BM-MSCs. CONCLUSIONS: We characterized the biological features, the immunomodulatory capacity and the gene expression profile of NB-MSCs. The NB-MSC gene expression profile and their functional properties suggest a potential role in promoting tumor escape, invasiveness and metastatic traits of NB cancer cells. A better understanding of the complex mechanisms underlying the interactions between NB cells and NB-derived MSCs should shed new light on potential novel therapeutic approaches.

Fibroblastos Associados a Câncer/metabolismo , Células-Tronco Mesenquimais/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Microambiente Tumoral , Biomarcadores Tumorais , Células da Medula Óssea/metabolismo , Fibroblastos Associados a Câncer/patologia , Ciclo Celular , Diferenciação Celular/genética , Separação Celular/métodos , Células Cultivadas , Pré-Escolar , Técnicas de Cocultura , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Imunofenotipagem/métodos , Lactente , Masculino , Mutação , Neuroblastoma/epidemiologia , Neuroblastoma/terapia , Vigilância da População , Sistema de Registros , Transdução de Sinais , Microambiente Tumoral/genética
Stem Cell Res Ther ; 8(1): 236, 2017 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-29058626


BACKGROUND: The use of stem cells, including mesenchymal stem cells (MSCs), for regenerative medicine is gaining interest for the clinical benefits so far obtained in patients. This study investigates the use of adipose autologous tissue in combination with platelet-rich plasma (PRP) to improve the clinical outcome of patients affected by systemic sclerosis (SSc). METHODS: Adipose-derived mesenchymal stem cells (AD-MSCs) and PRPs were purified from healthy donors and SSc patients. The multilineage differentiation potential of AD-MSCs and their genotypic-phenotypic features were investigated. A cytokine production profile was evaluated on AD-MSCs and PRPs from both healthy subjects and SSc patients. The adipose tissue-derived cell fraction, the so-called stromal vascular fraction (SVF), was coinjected with PRP in the perioral area of SSc patients. RESULTS: Histopathological and phenotypical analysis of adipose tissue from SSc patients revealed a disorganization of its distinct architecture coupled with an altered cell composition. Although AD-MSCs derived from SSc patients showed high multipotency, they failed to sustain a terminally differentiated progeny. Furthermore, SVFs derived from SSc patients differed from healthy donors in their MSC-like traits coupled with an aberrant cytokine production profile. Finally, the administration of PRP in combination with autologous SVF improved buccal's rhyme, skin elasticity and vascularization for all of the SSc patients enrolled in this study. CONCLUSIONS: This innovative regenerative therapy could be exploited for the treatment of chronic connective tissue diseases, including SSc.

Tecido Adiposo/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Plasma Rico em Plaquetas/fisiologia , Medicina Regenerativa/métodos , Escleroderma Sistêmico/terapia , Tecido Adiposo/imunologia , Adulto , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos CD/imunologia , Diferenciação Celular , Proliferação de Células , Terapia Baseada em Transplante de Células e Tecidos/métodos , Citocinas/genética , Citocinas/imunologia , Feminino , Expressão Gênica , Humanos , Masculino , Células-Tronco Mesenquimais/imunologia , Pessoa de Meia-Idade , Neovascularização Fisiológica , Cultura Primária de Células , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Pele/patologia
Artigo em Inglês | MEDLINE | ID: mdl-25120531


Recent discoveries highlight the emerging role of estrogens in the initiation and progression of different malignancies through their interaction with stem cell (SC) compartment. Estrogens play a relevant role especially for those tumors bearing a gender disparity in incidence and aggressiveness, as occurs for most thyroid diseases. Although several experimental lines suggest that estrogens promote thyroid cell proliferation and invasion, their precise contribution in SC compartment still remains unclear. This review underlines the interplay between hormones and thyroid function, which could help to complete the puzzle of gender discrepancy in thyroid malignancies. Defining the association between estrogen receptors' status and signaling pathways by which estrogens exert their effects on thyroid cells is a potential tool that provides important insights in pathogenetic mechanisms of thyroid tumors.