Low MUC4 expression is associated with survival benefit in patients with resectable pancreatic cancer receiving adjuvant gemcitabine

Urey, Carlos; Andersson, Bodil; Ansari, Daniel; Sasor, Agata; Said-Hilmersson, Katarzyna; Nilsson, Johan; Andersson, Roland

doi:10.1080/00365521.2017.1290134

Cited by 16 publications

(18 citation statements)

References 32 publications

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“…MUC4 is a type I membrane-bound mucin that promotes proliferation, motility, invasiveness, epithelial-mesenchymal transition, chemoresistance and tumour growth, the overexpression of which is considered an early event in pancreatic carcinogenesis, and is detected in the preneoplastic stage. Urey et al (30) investigated MUC4 expression by immunohistochemistry and indicated that low MUC4 expression is associated with a survival benefit in patients with resectable pancreatic cancer receiving adjuvant gemcitabine (30,31). However, no differences in MUC4 mutations were detected between samples in the long and short survival groups in the present study.…”

Section: Discussioncontrasting

confidence: 54%

Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis

et al. 2018

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Despite the genomic characterization of pancreatic cancer (PC), marked advances in the development of prognosis classification and novel therapeutic strategies have yet to come. The present study aimed to better understand the genomic alterations associated with the invasive phenotype of PC, in order to improve patient selection for treatment options. A total of 30 PC samples were analysed by either whole transcriptome (9 samples) or exome sequencing (21 samples) on an Illumina platform (75X2 or 100X2 bp), and the results were matched with normal DNA to identify somatic events. Single nucleotide variants and insertions and deletions were annotated using public databases, and the pathogenicity of the identified variants was defined according to prior knowledge and mutation-prediction tools. A total of 43 recurrently altered genes were identified, which were involved in numerous pathways, including chromatin remodelling and DNA damage repair. In addition, an analysis limited to a subgroup of early stage patients (50% of samples) demonstrated that poor prognosis was significantly associated with a higher number of known PC mutations (P=0.047). Samples from patients with a better overall survival (>25 months) harboured an average of 24 events, whereas samples from patients with an overall survival of <25 months presented an average of 40 mutations. These findings indicated that a complex genetic profile in the early stage of disease may be associated with increased aggressiveness, thus suggesting an urgent requirement for an innovative approach to classify this disease.

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Section: Discussioncontrasting

confidence: 54%

Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis

et al. 2018

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“…Furthermore, expression of mucins, and MUC4 in particular, has been related to resistance against Gemcitabine and other nucleoside analogues in pancreatic cancer cells (13)(14)(15)(16)(17). In a clinical setting, we were able to show that low expression of MUC4, compared to high MUC4 expression, confers a survival benefit for patients with resectable pancreatic tumors receiving adjuvant gemcitabine (18), further strengthening the role of MUC4 as a potential predictor of treatment response and a predictive biomarker.…”

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confidence: 49%

“…Mucins have previously been used as targets in cancer treatments, mainly as vaccines or immunotherapy (44). However, the choice of MUC4 might be debatable as MUC4 expression has also been directly related to Gemcitabine resistance of pancreatic cancer cells, both in a preclinical and clinical setting (15)(16)(17)(18). This could imply that a targeted gemcitabine-treatment might not be effective.…”

Section: Discussionmentioning

confidence: 89%

Development and In Vitro Characterization of a Gemcitabine-loaded MUC4-targeted Immunoliposome Against Pancreatic Ductal Adenocarcinoma

Urey

Hilmersson²,

Andersson³

et al. 2017

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Abstract. Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and devastating disease. In the US and the European countries, PDAC is the fourth leading cause of cancer-related death (1, 2). Incidence and mortality rates follow closely (3, 4) and even though the relative 5-year survival rate has improved slightly over the last years, it is still as low as 7% (2). Surgically removing the primary tumor, i.e. resection, is the only potential cure for PDAC. However, at the time of diagnosis, only around 20% of patients are eligible for surgical resection (5), and even so, most patients will relapse within five years (6). For patients with non-resectable tumors, the main treatment option is chemotherapy which mainly consists of a gemcitabine-based regimen, either alone or in combination with other drugs (7).Mucins belong to a large family of high molecular weight glycoproteins characterized by long tandem repeat regions rich in serine, proline and threonine (8). Mucins are expressed by various epithelial cells (9) while the human mucin family consists of 21 members, MUC1-MUC21. Based on their functions, mucins are further divided into two different subclasses, as either secreted or membrane-bound mucins (10). Secreted mucins can be divided into gelforming (MUC2, MUC5AC, MUC5B, MUC6) and non-gelforming (MUC7) (9). The secreted mucins form a physical barrier of mucous gel for protection of epithelial cells in the respiratory and GI tracts. Membrane-bound mucins (MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC13, MUC15, MUC16 and MUC17) are composed of a cytoplasmic tail and a transmembrane region and they contribute to the protective mucous gel through their single extracellular domain of O-glycosylated tandem repeats (8,10).In contrast to a healthy pancreas, which has weak or no mucin expression, pancreatic cancer is characterized by an aberrant expression of multiple mucins. During progression from normal pancreas to a malignant state, expression and glycosylation of both secreted and membrane-bound mucins are altered (10). Furthermore, altered expression of mucins is 6031 This article is freely accessible online.

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“…MUC4 expression in healthy tissues is mainly seen in epithelial cells of the airways and in secretory fluids such as saliva, breast milk and tears 42 , 84 . While MUC4 in normal pancreatic tissue has been consistently reported to be undetectable, expression has been observed in precursor lesions and increases during neoplastic progression, with positive expression in 70 to nearly 95% of PDAC cases 85 , 86 .…”

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confidence: 99%

Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer due to the relatively late diagnosis and the limited therapeutic options. Current treatment regimens mainly comprise the cytotoxic agents gemcitabine and FOLFIRINOX. These compounds have shown limited efficacy and severe side effects, highlighting the necessity for earlier detection and the development of more effective, and better-tolerated treatments. Although targeted therapies are promising for the treatment of several types of cancer, identification of suitable targets for early diagnosis and targeted therapy of PDAC is challenging. Interestingly, several transmembrane proteins are overexpressed in PDAC cells that show low expression in healthy pancreas and may therefore serve as potential targets for treatment and/or diagnostic purposes. In this review we describe the 11 most promising transmembrane proteins, carefully selected after a thorough literature search. Favorable features and potential applications of each target, as well as the results of the preclinical and clinical studies conducted in the past ten years, are discussed in detail.

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Low MUC4 expression is associated with survival benefit in patients with resectable pancreatic cancer receiving adjuvant gemcitabine

Abstract: This is the first study indicating a predictive role of MUC4 expression for gemcitabine treatment in the clinical setting.

Cited by 16 publications

References 32 publications

Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis

Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis

Development and In Vitro Characterization of a Gemcitabine-loaded MUC4-targeted Immunoliposome Against Pancreatic Ductal Adenocarcinoma

Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma

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