Current understanding of the molecular biology of pancreatic neuroendocrine tumors

Abstract

Pancreatic neuroendocrine tumors (PanNETs) are complicated and often deadly neoplasms. A recent increased understanding of their molecular biology has contributed to expanded treatment options. DNA sequencing of samples derived from patients with PanNETs and rare genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Von Hippel-Lindau (VHL) syndrome reveals the involvement of MEN1, DAXX/ATRX, and the mammalian target of rapamycin (mTOR) pathways in PanNET tumorigenesis. Gene knock-out/knock-in studies indicate that inactivation of factors including MEN1 and abnormal PI3K/mTOR signaling uncouples endocrine cell cycle progression from the control of environmental cues such as glucose, leading to islet cell overgrowth. In addition, accumulating evidence suggests that further impairment of endothelial-endocrine cell interactions contributes to tumor invasion and metastasis. Recent phase III clinical trials have shown that therapeutic interventions, such as sunitinib and everolimus, targeting those signal transduction pathways improve disease-free survival rates. Yet, cure in the setting of advanced disease remains elusive. Further advances in our understanding of the molecular mechanisms of PanNETs and improved preclinical models will assist in developing personalized therapy utilizing novel drugs to provide prolonged control or even cure the disease.

Figure 1.

Histological morphology of pancreatic neuroendocrine tumors (PanNETs) (adapted from PathPedia.com and Couvelard (1) with reproduction permissions). A) Pancreatic endocrine neoplasm, a neuroendocrine tumor of the pancreas with metastatic potential. Grossly, almost all tumors are well demarcated from the surrounding normal pancreas and may show a thin fibrous capsule. Microscopically, most tumors have a pushing margin as shown in this example with arrowheads. The tumor on the right “pushes” in to the nonneoplastic pancreatic parenchyma on the left of arrowheads. B) A pancreatic neuroendocrine carcinoma of large cell type, G3 (Ki-67 = 30%) (poorly differentiated endocrine carcinoma category according to the World Health Organization [WHO] 2010). Hematoxylin and eosin, ×10 objective. C) A liver metastasis of a pancreatic neuroendocrine tumor, G1 (Ki-67 <1%), stage IV according to WHO 2010. The 1-cm liver metastasis is well delineated. L = liver. Hematoxylin and eosin, ×10 objective.

Figure 2.

Control of the islet cell cycle. The endothelium provides extracellular matrix (ECM) and forms the capillary structure around the islets. Endocrine cells interact with ECM through integrin and laminin. Upon stimulation such as with glucose, G1/S progression occurs if there is no DNA damage (ie, low p53 levels). New cells release vascular endothelial growth factor (VEGF) to attract endothelial cells (ECs). Endocrine cells attach to ECs, triggering signaling cascades for growth. FAK = focal adhesion kinase; NFκB = nuclear factor kappa B; PAK = p21-activated kinase; Rac = ras-related C3 botulinum toxin substrate; Rho = rhodopsin; RAS = rat sarcoma.

Figure 3.

Common genetic mutations and impacted signal transduction pathways in pancreatic neuroendocrine tumors (PanNETs). A) Cell growth. MEN1 mutations decrease Menin-regulated p27/p18 expression, which abrogates the glucose sensor. DAXX mutations decrease p53 levels, diminishing the check point for cellular/DNA damages. Both MEN1 and DAXX mutations promote cell cycle progression from the G1 to S phase, regardless of glucose levels and damage. B) Cell–cell communications. Endocrine cells such as β or α cells rely on the endothelium to provide extracellular matrix. Thus, disabling the attachment requirement needed for cancer cells to invade and migrate. ATRX mutation-modulated chromatin modification may play a role in the abnormal activation of FAK/Src and mTOR pathways in PanNET. Underlines indicate the mutated genes or activated protein. EC = endothelial cell; FAK = focal adhesion kinase; HBA1 = hemoglobin-α; JNK = c-Jun N-terminal kinase; MEN1 = multiple endocrine neoplasia type 1; mTOR = mammalian target of rapamycin; NO = nitric oxide; PAK = p21-activated kinase; PI3K/Akt = phosphoinositide-3-kinase/protein kinase B.

Figure 4.

A double-hit model of pancreatic neuroendocrine tumors. The first hit: Mutation of the checkpoint genes such as multiple endocrine neoplasia type 1 and p53 causes constant cell cycle progression even under conditions of low glucose levels and DNA damage. Increased numbers of islet cells can elevate insulin levels and induce a stressful microenvironment due to oxygen and nutrient deficiency. The second hit: ATRX and mTOR gene mutation can cause cell growth in the absence of cell–cell interaction through constant activation of focal adhesion kinase/Src or inside-outside–associated signaling.

Figure 5.

Survival curves from RAD003 in Advanced Neuroendocrine Tumors (RADIANT-3) and RADIANT-2 clinical trials. A) RADIANT-3: Progression-free survival for everolimus-treated patients compared with control patients in a phase III randomized placebo-controlled trial. B) RADIANT-2: Progression-free survival for everolimus plus octreotide (E+O) vs placebo plus octreotide (P+O) in a phase III randomized placebo-controlled trial. The numbers of patients at risk at various time points are listed below the graphs. One-sided log-rank test was used to calculate P values. CI = confidence interval; HR = hazard ratio. Adapted from Yao et al. (102) and Pavel et al. (103) with reproduction permissions.