Recent progress in pancreatic cancer

Wolfgang, Christopher L.; Herman, Joseph M.; Laheru, Daniel A.; Klein, Alison P.; Erdek, Michael; Fishman, Elliot K.; Hruban, Ralph H.

doi:10.3322/caac.21190

Cited by 794 publications

(711 citation statements)

References 231 publications

(489 reference statements)

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“…Despite advances in early diagnosis and treatment of PC, the 5-year survival rate is less than 5% and the median survival is only 6 mo. 1 This neoplasm is often resistant to available therapeutic approaches such as radiotherapy and chemotherapy, in part because of frequent genomic alterations. 2 Currently, gemcitabine is the mainstay of therapy; however, response rates are less than 20%.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Feng

Jiang

et al. 2016

Autophagy

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In contrast to normal tissue, cancer cells display profound alterations in protein synthesis and degradation. Therefore, proteins that regulate endoplasmic reticulum (ER) homeostasis are being increasingly recognized as potential therapeutic targets. The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. However, interactions between autophagy, the proteasome, and ER stress pathways in cancer remain largely undefined. This study demonstrated that withaferin-A (WA), the biologically active withanolide extracted from Withania somnifera, significantly increased autophagosomes, but blocked the degradation of autophagic cargo by inhibiting SNARE-mediated fusion of autophagosomes and lysosomes in human pancreatic cancer (PC) cells. WA specifically induced proteasome inhibition and promoted the accumulation of ubiquitinated proteins, which resulted in ER stress-mediated apoptosis. Meanwhile, the impaired autophagy at early stage induced by WA was likely activated in response to ER stress. Importantly, combining WA with a series of ER stress aggravators enhanced apoptosis synergistically. WA was well tolerated in mice, and displayed synergism with ER stress aggravators to inhibit tumor growth in PC xenografts. Taken together, these findings indicate that simultaneous suppression of 2 key intracellular protein degradation systems rendered PC cells vulnerable to ER stress, which may represent an avenue for new therapeutic combinations for this disease.

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Section: Introductionmentioning

confidence: 99%

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Feng

Jiang

et al. 2016

Autophagy

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“…1 Recently, epidemiological and experimental data have demonstrated a close connection between chronic pancreatitis and pancreatic cancer. 2,3 However, the mechanisms involved are still far from defined.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

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Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Aca and PP2Acb isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-kB (NF-kB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Aca overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-kB pathway in vitro. LPS and MCM induced IKK and IkB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKa attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-kB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-kB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-kB pathway-dependent PP2Ac repression.

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“…In spite of significant cost-intensive research efforts, the 5-year survival rate for patients with pancreatic ductal adenocarcinoma (PDA) remains approximately 5 %, a statistic that has virtually not changed in the past 50 years. PDA is often diagnosed in an advanced stage with primary tumors invading surrounding structures and/or with distant metastases, leaving only palliative treatment options [19].…”

Section: Pancreatic Ductal Adenocarcinomamentioning

confidence: 99%

“…Although it is clear that there is a strong familial component to pancreatic cancer, a causative germline mutation in a known pancreatic cancer susceptibility gene can be identified in only approximately 20 % of familial cases [50,51]. The genes that are known to predispose to pancreatic cancer (Table 1) include genes causing hereditary breast-ovarian cancer (caused by germline mutations in BRCA1, BRAC2, or PALB2; with a relative risk of 3.5-10 for BRCA2), familial atypical multiple mole melanoma syndrome (caused by germline mutations in p16/CDKN2A; with a relative risk of [13][14][15][16][17][18][19][20][21][22], Peutz-Jeghers syndrome (caused by germline mutations in STK11; with a relative risk of 132), hereditary pancreatitis (caused by germline mutations in PRSS1 or SPINK1; with a relative risk of 50-80), Lynch syndrome (caused by germline mutations in MLH1, MSH2, etc. ; with a relative risk of 8.6) [47,51,52], and ataxia-telangiectasia (caused by germline mutations in ATM) [7,53,54].…”

Section: Pancreatic Ductal Adenocarcinomamentioning

confidence: 99%

The genetic classification of pancreatic neoplasia

2015

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Cancer is caused by the accumulation of inherited and/or acquired alterations in specific genes. The recent decline in the cost of DNA sequencing has allowed tumor sequencing to be conducted on a large scale, which, in turn, has led to an unprecedented understanding of the genetic events that drive neoplasia. This understanding, when integrated with meticulous histologic analyses and with clinical findings, has direct clinical implications. The recent sequencing of all of the major types of cystic and noncystic neoplasms of the pancreas has revealed opportunities for molecular diagnoses and for personalized treatment. This review summarizes the results from these recent studies focusing on the clinical relevance of genomic data.

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Recent progress in pancreatic cancer

Cited by 794 publications

References 231 publications

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

The genetic classification of pancreatic neoplasia

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