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Carcinogenesis of pancreatic adenocarcinoma: precursor lesions.

Gnoni A, Licchetta A, Scarpa A, Azzariti A, Brunetti AE, Simone G, Nardulli P, Santini D, Aieta M, Delcuratolo S, Silvestris N - Int J Mol Sci (2013)

Bottom Line: In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications.Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs.This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Unit, Hospital Vito Fazzi, Lecce 73100, Italy. n.silvestris@oncologico.bari.it.

ABSTRACT
Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor genes; changes in the cell cycle and pathways leading to apoptosis; and also changes in epithelial to mesenchymal transition. The most common alterations involve the epidermal growth factor receptor (EGFR) gene, the HER2 gene, and the K-ras gene. In particular, the loss of function of tumor-suppressor genes has been documented in this tumor, especially in CDKN2a, p53, DPC4 and BRCA2 genes. However, other molecular events involved in pancreatic adenocarcinoma pathogenesis contribute to its development and maintenance, specifically epigenetic events. In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs. In this scenario, highlighting these molecular alterations could provide new clinical tools for early diagnosis and new effective therapies for this malignancy.

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Precursor lesions in PDAC: correlation with oncogenes and tumor suppressor genes.
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f1-ijms-14-19731: Precursor lesions in PDAC: correlation with oncogenes and tumor suppressor genes.

Mentions: Three types of PDAC precursor lesions have been characterized in the last decade: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary neoplasia (IPMNs) and mucinous cystic neoplasms (MCNs). They all follow a multistep progression to invasive cancer characterized by increasing degrees of morphological and cytological atypia [7] (Figure 1). The following observations are in favor of a multistep carcinogenesis: duct lesions are far more common in pancreases with infiltrating carcinoma [8]; there is an increase in the grade of lesions surrounding infiltrating carcinoma [9]; patients diagnosed with intraductal mucinous neoplasms that are not resected subsequently develop infiltrating carcinoma [9]. All three known precursor lesions bear ductal epithelial cell characteristics, but the precise cellular origin of these lesions is still highly debated. The contribution of immature pancreatic precursors to PDAC progression raises the possibility of the presence of pancreatic cancer stem cells (CSC). These cells give rise to a heterogeneous lineage [10,11]. Indeed, CSC may derive from this particular population, to acquire a slightly transformed phenotype, known as “minimal deviation” [12]. The location and the rarity of these cells within the tumor would contribute to explain their resistance against conventional therapies, and there is a correlation with the “epithelial to mesenchymal transition” concept, explained below [11,13].


Carcinogenesis of pancreatic adenocarcinoma: precursor lesions.

Gnoni A, Licchetta A, Scarpa A, Azzariti A, Brunetti AE, Simone G, Nardulli P, Santini D, Aieta M, Delcuratolo S, Silvestris N - Int J Mol Sci (2013)

Precursor lesions in PDAC: correlation with oncogenes and tumor suppressor genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3821583&req=5

f1-ijms-14-19731: Precursor lesions in PDAC: correlation with oncogenes and tumor suppressor genes.
Mentions: Three types of PDAC precursor lesions have been characterized in the last decade: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary neoplasia (IPMNs) and mucinous cystic neoplasms (MCNs). They all follow a multistep progression to invasive cancer characterized by increasing degrees of morphological and cytological atypia [7] (Figure 1). The following observations are in favor of a multistep carcinogenesis: duct lesions are far more common in pancreases with infiltrating carcinoma [8]; there is an increase in the grade of lesions surrounding infiltrating carcinoma [9]; patients diagnosed with intraductal mucinous neoplasms that are not resected subsequently develop infiltrating carcinoma [9]. All three known precursor lesions bear ductal epithelial cell characteristics, but the precise cellular origin of these lesions is still highly debated. The contribution of immature pancreatic precursors to PDAC progression raises the possibility of the presence of pancreatic cancer stem cells (CSC). These cells give rise to a heterogeneous lineage [10,11]. Indeed, CSC may derive from this particular population, to acquire a slightly transformed phenotype, known as “minimal deviation” [12]. The location and the rarity of these cells within the tumor would contribute to explain their resistance against conventional therapies, and there is a correlation with the “epithelial to mesenchymal transition” concept, explained below [11,13].

Bottom Line: In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications.Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs.This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Unit, Hospital Vito Fazzi, Lecce 73100, Italy. n.silvestris@oncologico.bari.it.

ABSTRACT
Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor genes; changes in the cell cycle and pathways leading to apoptosis; and also changes in epithelial to mesenchymal transition. The most common alterations involve the epidermal growth factor receptor (EGFR) gene, the HER2 gene, and the K-ras gene. In particular, the loss of function of tumor-suppressor genes has been documented in this tumor, especially in CDKN2a, p53, DPC4 and BRCA2 genes. However, other molecular events involved in pancreatic adenocarcinoma pathogenesis contribute to its development and maintenance, specifically epigenetic events. In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs. In this scenario, highlighting these molecular alterations could provide new clinical tools for early diagnosis and new effective therapies for this malignancy.

Show MeSH
Related in: MedlinePlus