Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216

Mohelníková-Duchoňová, Beatrice; Kočík, Matěj; Duchonová, Beatrice Mohelníková; Brynychová, Veronika; Oliverius, Martin; Hlavsa, Jan; Honsová, Eva; Mazanec, Jan; Kala, Zdeněk; Ojima, Iwao; Hughes, David J.; Doherty, Joanne; Murray, Helena; Crockard, Martin; Lemstrova, Radmila; Souček, Pavel

doi:10.1038/tpj.2016.55

Cited by 15 publications

(21 citation statements)

References 41 publications

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“…Characteristics of the patient cohort are summarized in Table I . The tissue specimen collection and processing, and the data retrieval were as described previously ( 11 ).…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, and no targeted therapy is currently available. The aim of the present study was to investigate the prognostic significance of the expression of V-Ki-ras2 Κirsten rat sarcoma viral oncogene homolog (KRAS), downstream signaling pathway genes and the association with clinical characteristics in PDAC patients undergoing radical surgery. Tumors and adjacent non-neoplastic pancreatic tissues were examined in 45 patients with histologically verified PDAC. KRAS and B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene mutation analysis was performed using the KRAS/BRAF/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α array. The transcript profile of 52 KRAS downstream signaling pathway genes was assessed using quantitative-polymerase chain reaction. KRAS mutation was detected in 80% of cases. The genes of four signaling pathways downstream of KRAS, including the phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/V-akt murine thymoma viral oncogene homolog 1, RAL guanine nucleotide exchange factor, Ras and Rab interactor 1/ABL proto-oncogene-1, non-receptor tyrosine kinase, and RAF proto-oncogene serine/threonine-protein kinase/mitogen-activated protein kinase pathways, exhibited differential expression in PDAC compared with that in the adjacent normal tissues. However, no significant differences in expression were evident between patients with KRAS-mutated and wild-type tumors. The expression of KRAS downstream signaling pathways genes did not correlate with angioinvasion, perineural invasion, grade or presence of lymph node metastasis. Additionally, the presence of KRAS mutations was not associated with overall survival. Among the KRAS downstream effective signaling pathways molecules investigated, only v-raf-1 murine leukemia viral oncogene homolog 1 expression was predictive of prognosis. Overall, KRAS mutation is present in the majority of cases of PDAC, but is not associated with changes in the expression of KRAS downstream signaling pathways and the clinical outcome. This may partly explain the failure of KRAS-targeted therapies in PDAC.

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“…Characteristics of the patient cohort are summarized in Table I . The tissue specimen collection and processing, and the data retrieval were as described previously ( 11 ).…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome

et al. 2017

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“…The high levels of IHH in HAS3-EVs were surprising, given that most of the reported studies on melanoma and other cancers have largely implicated the role of SHH in the process [ 66 – 68 ]. However, IHH is a well-known stimulus for self-renewal and enhanced proliferation in several cancers, including colorectal [ 69 ], lung [ 70 ], pancreatic [ 71 ], gastric [ 72 ], and T cell acute lymphoblastic leukemia [ 73 ]. Our results also point out that knocking down IHH in MV3-GFP-HAS3 cells negatively impacts the HAS3-EVs ability to enable HA secretion in HaCaT cells and downregulation of HAS2 and HAS3 in MV3 parental cells decreases IHH secretion in EVs.…”

Section: Discussionmentioning

confidence: 99%

HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells

Arasu

Deen

Pasonen‐Seppänen

et al. 2019

Cell. Mol. Life Sci.

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Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.

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“…The cancer stem cell maintenance, tumor-stroma cross-talk, and chemo-resistance could also be affected by interactions between Hedgehog and other signaling pathways. Mohelnikova et al did not found any strong correlation between Hedgehog expression profile and KRAS mutation status in PDAC patients [ 118 ], regardless of previous PDAC studies [ 119 ]. Taxoid involvement with a dysregulated Hedgehog signaling pathway in patients with PDAC could have significant therapeutic benefits.…”

Section: Signaling Pathways Involved In Pcscsmentioning

confidence: 99%

“…Taxoid involvement with a dysregulated Hedgehog signaling pathway in patients with PDAC could have significant therapeutic benefits. New-generation taxoids can abrogate the overexpression of Hedgehog in pancreatic cancer [ 118 ]. Molecular interaction between WNT/β-catenin, Notch, TGF-β, and hedgehog indicates that during oncogenesis, two or more pathways crosstalk with each other.…”

Section: Signaling Pathways Involved In Pcscsmentioning

confidence: 99%

Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma

et al. 2021

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One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine′s action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.

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Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216

Cited by 15 publications

References 41 publications

Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome

Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome

HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells

Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma

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