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1.
Nat Rev Cancer ; 22(12): 703-722, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36253536

RESUMO

Growing evidence suggests that the gut microbiota modulates the efficacy and toxicity of cancer therapy, most notably immunotherapy and its immune-related adverse effects. The poor response to immunotherapy in patients treated with antibiotics supports this influential role of the microbiota. Until recently, results pertaining to the identification of the microbial species responsible for these effects were incongruent, and relatively few studies analysed the underlying mechanisms. A better understanding of the taxonomy of the species involved and of the mechanisms of action has since been achieved. Defined bacterial species have been shown to promote an improved response to immune-checkpoint inhibitors by producing different products or metabolites. However, a suppressive effect of Gram-negative bacteria may be dominant in some unresponsive patients. Machine learning approaches trained on the microbiota composition of patients can predict the ability of patients to respond to immunotherapy with some accuracy. Thus, interest in modulating the microbiota composition to improve patient responsiveness to therapy has been mounting. Clinical proof-of-concept studies have demonstrated that faecal microbiota transplantation or dietary interventions might be utilized clinically to improve the success rate of immunotherapy in patients with cancer. Here, we review recent advances and discuss emerging strategies for microbiota-based cancer therapies.


Assuntos
Microbioma Gastrointestinal , Microbiota , Neoplasias , Humanos , Microbioma Gastrointestinal/fisiologia , Imunoterapia/métodos , Transplante de Microbiota Fecal/métodos , Neoplasias/tratamento farmacológico
2.
Nat Med ; 28(3): 545-556, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35228752

RESUMO

Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with antitumor response to anti-programmed cell death protein-1 (PD-1) therapy, but inconsistencies exist between published microbial signatures associated with clinical outcomes. To resolve this, we evaluated a new melanoma cohort, along with four published datasets. Time-to-event analysis showed that baseline microbiota composition was optimally associated with clinical outcome at approximately 1 year after initiation of treatment. Meta-analysis and other bioinformatic analyses of the combined data show that bacteria associated with favorable response are confined within the Actinobacteria phylum and the Lachnospiraceae/Ruminococcaceae families of Firmicutes. Conversely, Gram-negative bacteria were associated with an inflammatory host intestinal gene signature, increased blood neutrophil-to-lymphocyte ratio, and unfavorable outcome. Two microbial signatures, enriched for Lachnospiraceae spp. and Streptococcaceae spp., were associated with favorable and unfavorable clinical response, respectively, and with distinct immune-related adverse effects. Despite between-cohort heterogeneity, optimized all-minus-one supervised learning algorithms trained on batch-corrected microbiome data consistently predicted outcomes to programmed cell death protein-1 therapy in all cohorts. Gut microbial communities (microbiotypes) with nonuniform geographical distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts. Our findings shed new light on the complex interaction between the gut microbiome and response to cancer immunotherapy, providing a roadmap for future studies.


Assuntos
Microbioma Gastrointestinal , Melanoma , Microbiota , Bactérias/genética , Microbioma Gastrointestinal/genética , Humanos , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico
3.
Science ; 371(6529): 595-602, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33542131

RESUMO

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Transplante de Microbiota Fecal , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/terapia , Linfócitos T CD8-Positivos/imunologia , Microbioma Gastrointestinal , Humanos , Interleucina-8/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Células Mieloides/imunologia , Microambiente Tumoral/imunologia
4.
Mol Cell Biol ; 26(22): 8418-26, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16954380

RESUMO

Inhibition of the mutationally activated Wnt cascade in colorectal cancer cell lines induces a rapid G1 arrest and subsequent differentiation. This arrest can be overcome by maintaining expression of a single Tcf4 target gene, the proto-oncogene c-Myc. Since colorectal cancer cells share many molecular characteristics with proliferative crypt progenitors, we have assessed the physiological role of c-Myc in adult crypts by conditional gene deletion. c-Myc-deficient crypts are lost within weeks and replaced by c-Myc-proficient crypts through a fission process of crypts that have escaped gene deletion. Although c-Myc(-/-) crypt cells remain in the cell cycle, they are on average much smaller than wild-type cells, cycle slower, and divide at a smaller cell size. c-Myc appears essential for crypt progenitor cells to provide the necessary biosynthetic capacity to successfully progress through the cell cycle.


Assuntos
Neoplasias Colorretais/metabolismo , Genes myc , Intestinos/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição TCF/genética , Proteínas Wnt/genética , Animais , Apoptose , Contagem de Células , Neoplasias Colorretais/patologia , Epitélio/fisiologia , Marcação de Genes , Integrases/genética , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mitose , Proteína 2 Semelhante ao Fator 7 de Transcrição
5.
Sci Transl Med ; 10(454)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111642

RESUMO

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor-ß1 (TGFß1) ligand. In acetaminophen poisoning, inhibition of TGFß receptor 1 (TGFßR1) improved mouse survival. TGFßR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.


Assuntos
Senescência Celular , Regeneração Hepática , Fígado/lesões , Fígado/fisiopatologia , Comunicação Parácrina , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Modelos Animais de Doenças , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/patologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Necrose , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
6.
Nat Cell Biol ; 17(8): 971-983, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26192438

RESUMO

Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.


Assuntos
Ductos Biliares/transplante , Linhagem da Célula , Proliferação de Células , Células Epiteliais/transplante , Hepatócitos/transplante , Regeneração Hepática , Fígado , Transplante de Células-Tronco , Células-Tronco , Animais , Apoptose , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Biomarcadores/metabolismo , Separação Celular , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Genótipo , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Fenótipo , Proteínas Proto-Oncogênicas c-mdm2/deficiência , Proteínas Proto-Oncogênicas c-mdm2/genética , Células-Tronco/metabolismo , Células-Tronco/patologia , Fatores de Tempo
9.
EMBO Mol Med ; 2(11): 472-86, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20976827

RESUMO

Senescence has been implicated as an important mechanism of tumour suppression in a number of human malignancies, including colorectal cancer (CRC). However, we still have a relatively poor understanding of how the underlying mutations that occur in cancer cause senescence and its relevance in vivo. The Apc gene is mutated in approximately 80% of CRC as the initiating event, but rarely elsewhere. In this study we have examined the capacity of Apc loss to induce senescence in the intestinal epithelium compared to the renal epithelium. Within the renal epithelium, loss of Apc function led to an induction of senescence, however, bypassing senescence through combined Apc and p21 or Ink4A gene deletion rapidly initiated renal carcinoma. Within the intestinal epithelium, loss of Apc did not induce senescence. Moreover, combined Apc and p21 or Ink4A loss had no impact upon tumourigenesis. Taken together, these results show that Apc loss in vivo invokes a senescence program in a context-dependent fashion, and implies senescence may play a key barrier to tumourigenesis in the kidney. However, in CRC, escape from senescence is likely to only be a barrier in cancers initiated by other mutations.


Assuntos
Proteína da Polipose Adenomatosa do Colo/deficiência , Envelhecimento , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Epitélio/fisiopatologia , Intestinos/fisiopatologia , Rim/fisiopatologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Deleção de Genes , Histocitoquímica , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia
10.
Cancer Res ; 70(20): 8149-58, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20736363

RESUMO

Inactivation of the Apc gene is recognized as the key early event in the development of sporadic colorectal cancer (CRC), where its loss leads to constitutive activation of ß-catenin/T-cell factor 4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and other previous studies have shown that although cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting that proliferation following acute Apc loss may be dependent on another D-type cyclin. In this study, we investigated the expression and functional relevance of cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in cyclin-dependent kinase 4 (CDK4) and hyperphosphorylated Rb levels. Deficiency of cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc-deficient intestinal epithelium. Moreover, cyclin D2 dramatically reduced tumor growth and development in Apc(Min/+) mice. Importantly, cyclin D2 knockout did not affect proliferation of normal enterocytes, and furthermore, CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from Apc(Min/+) mice. Taken together, these results indicate that cyclin D-CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling, and inhibiting this complex may be an effective chemopreventative strategy in CRC.


Assuntos
Adenoma/patologia , Ciclina D2/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Genes APC , Adenoma/genética , Animais , Apoptose , Divisão Celular , Ciclina D2/deficiência , Ciclina D2/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Primers do DNA , Deleção de Genes , Genes myc , Imuno-Histoquímica , Polipose Intestinal/genética , Polipose Intestinal/patologia , Camundongos , Índice Mitótico , Reação em Cadeia da Polimerase , Regulação para Cima
11.
Proc Natl Acad Sci U S A ; 103(38): 14122-7, 2006 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-16959882

RESUMO

Oncogenic mutations in the K-ras gene occur in approximately 50% of human colorectal cancers. However, the precise role that K-ras oncogenes play in tumor formation is still unclear. To address this issue, we have conditionally expressed an oncogenic K-ras(V12) allele in the small intestine of adult mice either alone or in the context of Apc deficiency. We found that expression of K-ras(V12) does not affect normal intestinal homeostasis or the immediate phenotypes associated with Apc deficiency. Mechanistically we failed to find activation of the Raf/MEK/ERK pathway, which may be a consequence of the up-regulation of a number of negative feedback loops. However, K-ras(V12) expression accelerates intestinal tumorigenesis and confers invasive properties after Apc loss over the long term. In renal epithelium, expression of the oncogenic K-ras(V12) allele in the absence of Apc induces the rapid development of renal carcinoma. These tumors, unlike those of intestinal origin, display activation of the Raf/MEK/ERK and Akt signaling pathways. Taken together, these data indicate that normal intestinal and kidney epithelium are resistant to malignant transformation by an endogenous K-ras oncogene. However, activation of K-ras(V12) after Apc loss results in increased tumorigenesis with distinct kinetics. Whereas the effect of K-ras oncogenes in the intestine can been observed only after long latencies, they result in rapid carcinogenesis in the kidney epithelium. These data imply a window of opportunity for anti-K-ras therapies after tumor initiation in preventing tumor growth and invasion.


Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Transformação Celular Neoplásica , Neoplasias Colorretais , Genes ras , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Apoptose , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Homeostase , Humanos , Intestinos/citologia , Intestinos/patologia , Intestinos/fisiologia , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Transdução de Sinais/fisiologia , Taxa de Sobrevida , Quinases raf/metabolismo
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