At present, surgery remains the first line of treatment. Due to distant metastasis or local extension of the tumor, surgery is often non-curative. In advanced cases, surgical extraction of PanNETs can only reduce symptoms related to tumor suppression and hormone production 6. For patients who are not candidates for surgery, systemic treatment plays an important role in controlling the disease 7 , including targeted therapies, chemotherapy, somatostatin analogues and liver-directed therapies 8.
The mammalian target of rapamycin mTOR inhibitor everolimus and the antiangiogenic agent sunitinib are new targeted agents for advanced, unresectable or metastatic PanNETs and both have demonstrated efficacy and safety in clinical studies 9 , Nevertheless, primary and acquired resistance to these targeted therapies exists 11 and new anticancer strategies are urgently needed.
Cancer stem cells CSCs were first identified in a mouse tumor and later were found in solid tumors and leukemia 12 - Properties of CSCs include self-renewal, dedifferentiation, tumorigenicity and inherent chemotherapy resistance 18 , 19 , which may explain the drug resistance, metastasis and relapse risk of PanNETs. The potential new therapies may improve drug sensitivity and inhibit invasion and metastasis of PanNETs. These markers aided in identifying the CSCs, but there were no unique markers for specific cancers.
In , CSCs were identified in gastrointestinal neuroendocrine tumors The existence of CSCs in neuroendocrine tumor was validated by sphere formation assays in vitro and tumorigenicity assays in vivo. Research of CSCs in PanNETs is a relatively new area compared to the study of CSCs in leukemia 20 , in which therapy against progenitor populations has been applied to clinical settings. Once activated, Src participates in the regulation of normal and oncogenic processes.
It functions during tumor progression, with effects on apoptosis, cell adhesion, cell growth, cell migration and invasion The Notch pathway is essential in embryonic pancreatic development.
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Notch1 is expressed in the endodermal epithelium at early embryonic stages, and Notch2 is restricted to embryonic ducts, which might be the source of stem cells in a mouse model Mice deficient for delta-like gene 1 Dll1 showed accelerated differentiation of pancreatic endocrine cells and impaired normal pancreatic proliferation In human beings, Notch signaling has been demonstrated to regulate the differentiation of stem and progenitor cells in the development of pancreas 66 , The role of Notch signaling in CSC is uncertain, partially because activated Notch signaling has been identified as both a tumor promoter and suppressor in different tissues The Notch pathway inhibitor can reduce the proliferation of breast CSCs 69 and tumor recurrence in colorectal cancer patients At the same time, Notch signaling plays a role in regulating intestinal crypt fate There is no expression for CD in the body or fundic type glands or in intestinal metaplastic mucosa of stomach.
C In non-neoplastic pancreas, luminal pattern of CD expression is observed in small pancreatic ducts and centroacinar cells thin arrows , however, there is no immunoreactivity for CD in the pancreatic islets thick arrow points to the pancreatic islet which is encircled by a imaginary dentate line and appears clearer than surrounding exocrine parenchyma. D In non-neoplastic liver, CD immunohistochemical expression is observed along the luminal side of the cell membrane in small bile ducts and ductules arrows , while hepatocytes are exclusively devoid of CD expression.
The combination of cytoplasmic and luminal staining is also observed E, MANEC of pancreas that shows type V growth pattern thin arrows show luminal staining and thick arrows show cytoplasmic staining. The correlation of the immunohistochemical expression of CD according to the growth pattern of tumor cells is summarized in Patterns of CD immunohistochemical expression according to the tumor growth patterns. The distribution of CD immunohistochemical expression in NENs of different organs included in this study is demonstrated in The distribution of CD immunohistochemical expression according to WHO classification and tumor location.
Crosstable of immunohistochemical expression of CD according to the expression of neuroendocrine markers. The survival analysis, adjusted for age and tumor stage, was performed for 23 patients with NECs who had available follow-up data. Lardon, J. Pancreas , 36, e FEBS Lett.
Stem Cells in Neuroendocrinology
Immervoll, H. BMC Cancer , 8, Fan, L. BMC Cancer , 11, Sasaki, A. Jao, S. Kojima, M.
Stem Cells in Neuroendocrinology
Cancer Sci. Corbeil, D. Localization of this molecule in different cellular compartments by immunohistochemistry has led to the assumption that it may have specific functional role in the membrane and cytoplasm. Giebel, B.
Blood , , Lathia, J. Cell Death Dis. Xu, Y. USA , 81, Piyathilake, C. The other epitope is AC Initially generated to target CD surface antigen, AC has been lately used to identify cancer stem cells in several types of solid tumors. Blood , 90, Ying, X. The NENs in different organs arise from the neuroendocrine cells that are located in that area and they reveal the same immunohistochemical profile as the cells that they arise from. However, we did not observe CD positivity in the non-neoplastic endocrine cells, neither in those that are scattered throughout the gastrointestinal tract mucosa nor in the pancreatic islets.
We further evaluated the expression of CD in non-neoplastic parenchyma of pancreas in 15 cases of ductal adenocarcinoma of pancreas, in none of which the pancreatic islet showed immunoreactivity to CD data not shown. These findings indicate that CD is not a marker for normal neuroendocrine cells. On the contrary, the expression of CD was observed in NENs of various organs and of different histologic grade.
The significance of such expression however remains to be clarified in future in-depth and comprehensive studies.
Pituitary stem cell regulation: who is pulling the strings?
The survival analysis of patients with NENs especially the well-differentiated NETs G1 and G2 is associated with certain difficulties due to different reasons. Edge, S. Qiu, X.
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