KRAS-related proteins in pancreatic cancer

Mann, Karen; Ying, Haoqiang; Juan, Joseph; Jenkins, Nancy A.; Copeland, Neal G.

doi:10.1016/j.pharmthera.2016.09.003

Cited by 160 publications

(132 citation statements)

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“…Desmoplastic reaction, a dominant character of PDAC, is formed by the activation of pancreatic stellate cells (PSCs), which synthesize and secrete large amounts of extracellular matrix (ECM) [5]. Kras is one of the most common genes mutated in PDAC and plays a crucial role in the initiation and progression of PDAC, in which Kras mutation occurs in more than 90% of patients [6]. Somatic mutations in the Trp53 tumor suppressor gene are another frequent genetic event that drives PDAC progression.…”

Section: Introductionmentioning

confidence: 99%

Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer

et al. 2017

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer.MethodsLSL-KrasG12D/+; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-KrasG12D/+; Trp53fl/+; Pdx1-Cre (KPC) mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein.ResultsFollowing metformin treatment, pancreatic acinar-to-ductal metaplasia (ADM) and mouse pancreatic intraepithelial neoplasia (mPanIN) were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 (CK19)-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson’s trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival.ConclusionsMetformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0701-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer

et al. 2017

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“…Once mutated, KRAS remains in a continuously active state, interacting with diverse downstream effectors and signaling pathways associated with growth, invasion, and metastasis . Targeting of the downstream effectors of KRAS , particularly the MAPK and PI3K‐AKT signaling pathways, represents a promising strategy to prevent PDAC progression . Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is a member of the STAT protein family encoded by the STAT3 gene.…”

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confidence: 99%

“…(8,9) Targeting of the downstream effectors of KRAS, particularly the MAPK and PI3K-AKT signaling pathways, represents a promising strategy to prevent PDAC progression. (10) Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is a member of the STAT protein family encoded by the STAT3 gene. Activation of STAT3 may occur through phosphorylation by MAPK (11) and PI3K (12) signaling pathways.…”

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confidence: 99%

Dermokine contributes to epithelial–mesenchymal transition through increased activation of signal transducer and activator of transcription 3 in pancreatic cancer

Huang¹,

Xiang²,

Chen³

et al. 2017

Cancer Science

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Dermokine (DMKN) was first identified in relation to skin lesion healing and skin carcinoma. Recently, its expression was associated with pancreatic cancer tumorigenesis, although its involvement remains poorly understood. Herein, we showed that DMKN loss of function in Patu‐8988 and PANC‐1 pancreatic cancer cell lines resulted in reduced phosphorylation of signal transducer and activator of transcription 3, and increased activation of ERK1/2 and AKT serine/threonine kinase. This decreased the proliferation ability of pancreatic ductal adenocarcinoma (PDAC) cells. In addition, DMKN knockdown decreased the invasion and migration of PDAC cells, partially reversed the epithelial–mesenchymal transition, retarded tumor growth in a xenograft animal model by decreasing the density of microvessels, and attenuated the distant metastasis of human PDAC in a mouse model. Taken together, these data suggested that DMKN could be a potential prognostic biomarker and therapeutic target in pancreatic cancer.

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“…Activation of the PI3K/AKT and MEK/ERK pathways is common in different types of cancer (20)(21)(22)(23) and, in solid tumors, it is often associated with poor prognosis (24). AKT and ERK play crucial roles in cell proliferation, metastasis, angiogenesis, and drug response.…”

Section: Discussionmentioning

confidence: 99%

Effects of PHA-665752 and vemurafenib combination treatment on inï¿½vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations

Zhi

et al. 2018

Oncol Lett

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Abstract. It remains unknown whether blockade of B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E signaling and MET proto-oncogene, receptor tyrosine kinase (c-Met) signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. The present study investigated the effects of the vemurafenib alone and in combination with c-Met inhibitor PHA-665752 on the growth of human CRC cells in vitro and in mouse xenografts. HT-29 and RKO CRC cell lines with BRAF V600E mutations and mice bearing HT-29 xenografts were treated with vemurafenib in the absence or presence of PHA-665752. Cell viability and cycle phase were respectively examined by using the MTT and flow cytometry assay. Immunohistochemistry was conducted to detect the protein expression levels of hepatocyte growth factor (HGF), phosphorylated (p)-c-Met, p-AKT serine/threonine kinase (AKT) and p-extracellular signal-regulated kinase (p-ERK). The MTT assay demonstrated that the growth of RKO and HT-29 cells was inhibited by PHA-665752 in a time-and dose-dependent manner (P<0.05), however no significant suppressive effects were observed with vemurafenib. Relative to the PHA-665752 or vemurafenib stand-alone treatment groups, the combination of PHA-665752 and vemurafenib had a significant inhibitory effect on the proliferation of CRC cell lines (P<0.05). The mean tumor volume in mice treated with vemurafenib in combination with PHA-665752 was significantly smaller compared with those treated with only vemurafenib or PHA-665752 (P<0.05). Flow cytometry assay revealed that the G0/G1 phase frequency was significantly increased in the combination group compared with any other treatment groups (P<0.05). Immunohistochemistry demonstrated that vemurafenib in combination with PHA-665752 effectively induced the expression of p-c-Met, p-AKT and p-ERK, however had no effect on HGF. IntroductionColorectal cancer (CRC) is one of the principal causes of cancer worldwide (1). Unfortunately, even if a 5-year survival prognosis can be given to 90% of patients in the early stages, disappointing treatment outcomes are recorded in subjects with extensive local invasion or distant metastases. Generally, their 5-year survival rate is less than 15% (2) and, even if suitable for receiving adjuvant chemotherapy, disease-related deaths remain stubbornly high.A recent steady stream of important breakthroughs has dramatically improved our understanding of CRC. One such discovery identified the BRAF mutation as common in metastatic CRC patients, especially those with a right-side colon cancer and a poorly differentiated tumor (3). Vemurafenib is a potent and selective inhibitor of mutated BRAF. Chapman et al (4) revealed that vemurafenib achieved 40% response rates in melanoma with a BRAF mutation. However, unlike melanoma, the effect of vemurafenib in CRC patients with a BRAF mutation is often negligible, resulting in a clinical response in only 5% of patients (5). This discrepancy of outcomes suggests that different cancer types may present important variat...

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KRAS-related proteins in pancreatic cancer

Cited by 160 publications

References 136 publications

Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer

Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer

Dermokine contributes to epithelial–mesenchymal transition through increased activation of signal transducer and activator of transcription 3 in pancreatic cancer

Effects of PHA-665752 and vemurafenib combination treatment on inï¿½vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations

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