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1.
Cancer Gene Ther ; 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39448803

RESUMO

Tumor invasion is the hallmark of tumor malignancy. The invasive infiltration pattern of tumor cells located at the leading edge is highly correlated with metastasis and unfavorable patient outcomes. However, the regulatory mechanisms governing tumor malignancy at the invasive margin remain unclear. The IL-17B/IL-17RB pathway is known to promote pancreatic cancer invasion and metastasis, yet the specific mechanisms underlying IL-17RB upregulation during invasion are poorly understood. In this study, we unveiled a multistep process for IL-17RB upregulation at the invasive margin, which occurs through direct communication between tumor cells and fibroblasts. Tumor ATP1A1 facilitates plasma membrane expression of SEMA7A, which binds to and induces IGFBP-3 secretion from fibroblasts. The resulting gradient of IGFBP-3 influences the direction and enhances IL-17RB expression to regulate SNAI2 in invasion. These findings highlight the importance of local tumor-fibroblast interactions in promoting cancer cell invasiveness, potentially leading to the development of new therapeutic strategies targeting this communication.

2.
Br J Cancer ; 130(7): 1096-1108, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38341509

RESUMO

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. METHODS: We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)-positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)-AGR2 axis in mediating communication between CAFs and PNET cells was investigated. RESULTS: αSMA-positive and platelet-derived growth factor-α-positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis. CONCLUSION: CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4-SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.


Assuntos
Fibroblastos Associados a Câncer , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Fibroblastos Associados a Câncer/metabolismo , Tumores Neuroendócrinos/patologia , Linhagem Celular Tumoral , Neoplasias Pancreáticas/patologia , Tumores Neuroectodérmicos Primitivos/metabolismo , Tumores Neuroectodérmicos Primitivos/patologia , Microambiente Tumoral , Fibroblastos/metabolismo , Mucoproteínas/metabolismo , Mucoproteínas/uso terapêutico , Proteínas Oncogênicas/metabolismo
3.
Adv Sci (Weinh) ; 10(36): e2301240, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37964407

RESUMO

Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.


Assuntos
Carcinoma in Situ , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Camundongos , Humanos , Animais , Proteínas Proto-Oncogênicas p21(ras)/genética , Mucina-4 , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Camundongos Transgênicos , Carcinoma in Situ/genética , Carcinoma in Situ/patologia
4.
Mol Oncol ; 17(8): 1628-1647, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37171030

RESUMO

Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC), play an important role in tumorigenesis, metastasis, and chemoresistance. Tumor-derived small extracellular vesicles (sEVs), which mediate cell-to-cell communication between cancer cells and fibroblasts, are also critical for cancer progression and metastasis. However, it remains unclear how PDAC cell-derived sEVs activate fibroblasts, which contributes to tumor progression. Here, we report that ezrin (EZR) expression in PDAC cell-derived sEVs (sEV-EZR) can activate fibroblasts, resulting in increased migration ability and high expression of α-SMA, PDGFRB, and high production of extracellular matrix in fibroblasts. Reciprocally, sEV-EZR-activated fibroblasts enhanced PDAC cell proliferation, invasion, and metastasis to the liver in animal models. Conversely, fibroblasts treated with PDAC cell-derived sEVs with EZR knockdown resulted in the reduced metastatic ability of PDAC. Mechanistically, we demonstrated that PDAC cell-derived sEV-EZR increases the STAT3 and YAP-1 signaling pathways to induce fibroblast activation, and the activated fibroblasts promote PDAC cell proliferation, invasion, and liver metastasis. Inhibition of the STAT3 and YAP-1 signaling pathways by gene knockdown can abrogate sEV-EZR-induced effects. These findings suggest that targeting the interaction between PDAC cell-derived sEV-EZR and fibroblasts is a potential therapeutic strategy for PDAC.


Assuntos
Adenocarcinoma , Fibroblastos Associados a Câncer , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/genética , Adenocarcinoma/patologia , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral , Neoplasias Pancreáticas
5.
Nat Commun ; 13(1): 2945, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35618735

RESUMO

Tumor cells with diverse phenotypes and biological behaviors are influenced by stromal cells through secretory factors or direct cell-cell contact. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia with fibroblasts as the major cell type. In the present study, we observe enrichment of myofibroblasts in a juxta-tumoral position with tumor cells undergoing epithelial-mesenchymal transition (EMT) that facilitates invasion and correlates with a worse clinical prognosis in PDAC patients. Direct cell-cell contacts forming heterocellular aggregates between fibroblasts and tumor cells are detected in primary pancreatic tumors and circulating tumor microemboli (CTM). Mechanistically, ATP1A1 overexpressed in tumor cells binds to and reorganizes ATP1A1 of fibroblasts that induces calcium oscillations, NF-κB activation, and activin A secretion. Silencing ATP1A1 expression or neutralizing activin A secretion suppress tumor invasion and colonization. Taken together, these results elucidate the direct interplay between tumor cells and bound fibroblasts in PDAC progression, thereby providing potential therapeutic opportunities for inhibiting metastasis by interfering with these cell-cell interactions.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Ativinas , Carcinoma Ductal Pancreático/patologia , Comunicação Celular , Transição Epitelial-Mesenquimal/genética , Humanos , Miofibroblastos/metabolismo , Neoplasias Pancreáticas/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Neoplasias Pancreáticas
6.
Sci Transl Med ; 13(583)2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658352

RESUMO

The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphorylated IL-17RB in tumor specimens obtained from patients with pancreatic cancer correlated with worse prognosis. Phosphorylated IL-17RB recruits the ubiquitin ligase tripartite motif containing 56 to add lysine-63-linked ubiquitin chains to lysine-470 of IL-17RB, which further assembles NF-κB activator 1 (ACT1) and other factors to propagate downstream oncogenic signaling. Consequentially, IL-17RB mutants with substitution at either tyrosine-447 or lysine-470 lose their oncogenic activity. Treatment with a peptide consisting of amino acids 403 to 416 of IL-17RB blocks MLK4 binding, tyrosine-477 phosphorylation, and lysine-470 ubiquitination in vivo, thereby inhibiting tumorigenesis and metastasis and prolonging the life span of mice bearing pancreatic tumors. These results establish a clear pathway of how proximal signaling of IL-17RB occurs and provides insight into how this pathway provides a therapeutic target for pancreatic cancer.


Assuntos
Neoplasias Pancreáticas , Receptores de Interleucina-17 , Animais , Carcinogênese , Humanos , Camundongos , NF-kappa B/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais
7.
Am J Transl Res ; 8(4): 1626-40, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27186289

RESUMO

NPGPx (GPx7) is a member of the glutathione peroxidase (GPx) family without any GPx activity. GPx7 displays a unique function which serves as a stress sensor/transmitter to transfer the signal to its interacting proteins by shuttling disulfide bonds in response to various stresses. In this review, we focus on the exceptional structural and biochemical features of GPx7 compared to other 7 family members and described how GPx7 regulates the diverse signaling targets including GRP78, PDI, CPEB2, and XRN2, and their different roles in unfolded protein response, oxidative stress, and non-targeting siRNA stress response, respectively. The phenotypes associated with GPx7 deficiency in mouse or human including ROS accumulations, highly elevated cancer incidences, auto-immune disorders, and obesity are also revealed in this paper. Finally, we compare GPx8 with GPx7, which shares the highest structural similarity but different biological roles in stress response. These insights have thus provided a more comprehensive understanding of the role of GPx7 in the maintenance of redox homeostasis.

8.
Vet Ophthalmol ; 17(6): 432-42, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24171811

RESUMO

OBJECTIVE: To evaluate for drugs with superior neuroprotective efficacy and investigate their underlying mechanisms related to antioxidation. PROCEDURES: Brinzolamide (1%), timolol (0.5%), minocycline (22 mg/kg), lidocaine (1.5 mg/kg), and methylprednisolone (30 mg/kg) were administered to Sprague-Dawley (SD) rats. The retina was evaluated by electroretinography and histological analysis. The antioxidative capacity of drugs was evaluated to clarify the underlying mechanism. The oxidant/antioxidant profiles of plasma, red blood cells, and retina were analyzed by lipid peroxidation (malondialdehyde) and by measuring the activities of antioxidants. Proteomic analysis was used to investigate the possible protective mechanisms of the drug against ischemia-reperfusion injury. RESULTS: The results suggested that timolol, methylprednisolone, and minocycline protected retinal function. Methylprednisolone and minocycline possessed good antioxidative activity. Brinzolamide and lidocaine preserved the structural integrity of the retina, but not retinal function. CONCLUSION: Methylprednisolone, minocycline, and timolol have potential acute or delayed benefit in retinal ischemia-reperfusion injury. Their neuroprotective actions depend at least partially on the ability to alleviate oxidative stress.


Assuntos
Fármacos Neuroprotetores/uso terapêutico , Hipertensão Ocular/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Doenças Retinianas/etiologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Peroxidação de Lipídeos , Masculino , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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