RESUMO
BACKGROUND: Inflammation is a hallmark of cancer, and systemic markers of inflammation are increasingly recognised as negative prognostic factors for clinical outcome. Neutrophil-to-lymphocyte ratio (NLR) is readily available from routine blood testing of patients diagnosed with cancer. METHODS: Peer-reviewed publications from PubMed/MEDLINE, Web of Science and EMBASE were identified according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Hazard ratios (HR) for overall survival (OS) and surrogate endpoints (SE; comprising disease-, recurrence- and progression-free survival) were pooled using a random effects model. Additional analysis was carried out to further investigate NLR as an independent prognostic factor and account for heterogeneity. RESULTS: Seventy-one eligible papers comprising 32,788 patients were identified. High NLR was associated with poor clinical outcomes. Significant publication bias was observed, and larger studies also adjusted for more covariates. Correcting for publication bias in multivariate studies brought our best estimate for true effect size to HR = 1.57 (95% CI 1.39-1.78; p < 0.0001) for OS and to HR = 1.38 (95% CI 1.16-1.64; p = 0.0003) for SE. CONCLUSIONS: NLR is confirmed as an easily available prognostic biomarker in colorectal cancer, despite the limitations of some studies previously reporting this finding. As such, it should be routinely collected in prospective clinical trials. While more standardised and rigorous large-scale studies are needed before high NLR can be fully assessed as an independent predictor of CRC progression and outcome, the data suggest that it may be used to highlight individuals with tumour-promoting inflammatory context.
Assuntos
Neoplasias Colorretais/sangue , Linfócitos/metabolismo , Neutrófilos/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
RAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine and the mechanisms of how they contribute to tumourigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine, via induction of EGFR internalisation. Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to influencing stem cell proliferation during damage-induced intestinal regeneration, this role of RAL GTPases impacts on EGFR-dependent tumourigenic growth in the intestine and in human mammary epithelium. However, the effect of oncogenic RAS in the intestine is independent from RAL function. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of adult tissue homeostasis and malignant transformation.
Assuntos
Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Receptores ErbB/metabolismo , Mucosa Intestinal/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Receptores de Peptídeos de Invertebrados/metabolismo , Células-Tronco/metabolismo , Proteínas ral de Ligação ao GTP/metabolismo , Animais , Animais Geneticamente Modificados , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Endocitose , Receptores ErbB/genética , Feminino , Humanos , Hiperplasia , Mucosa Intestinal/patologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Glândulas Mamárias Humanas/enzimologia , Glândulas Mamárias Humanas/patologia , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Monoméricas de Ligação ao GTP/genética , Receptores de Peptídeos de Invertebrados/genética , Transdução de Sinais , Células-Tronco/patologia , Proteínas ral de Ligação ao GTP/genéticaRESUMO
Ral GTPases are RAS effector molecules and by implication a potential therapeutic target for RAS mutant cancer. However, very little is known about their roles in stem cells and tissue homeostasis. Using Drosophila, we identified expression of RalA in intestinal stem cells (ISCs) and progenitor cells of the fly midgut. RalA was required within ISCs for efficient regeneration downstream of Wnt signaling. Within the murine intestine, genetic deletion of either mammalian ortholog, Rala or Ralb, reduced ISC function and Lgr5 positivity, drove hypersensitivity to Wnt inhibition, and impaired tissue regeneration following damage. Ablation of both genes resulted in rapid crypt death. Mechanistically, RALA and RALB were required for efficient internalization of the Wnt receptor Frizzled-7. Together, we identify a conserved role for RAL GTPases in the promotion of optimal Wnt signaling, which defines ISC number and regenerative potential.