Table 2.
Genetically engineered pNET mouse models.
| Model | Strain | pNET Type | Key Findings |
|---|---|---|---|
| RIP-Tag2 | C57BL/6 | Insulinoma | SV40 large T-antigen inactivates p53 and Rb in islet-β cells and promotes insulinoma development in a multi-stage, synchronized fashion [57] |
|
Men1f/f Ptenf/f; MIP-Cre or RIP-Cre (MPM or MPR) |
C57BL/6J | Insulinoma | Loss of Pten co-operates with that of Men1 to develop well differentiated G1/G2 pNETs [56] |
| RIP-Tag2 AB6F1 | AB6F1 (hybrids from A/J dam and RT2 C57BL/6 sire) | Non-functional (NF) pNETs | RT2 mice develop NF pNETs with higher rate of liver metastases on AB6F1 genetic background, which is attributed to low expression of Insm1, a β-cell specific differentiation factor required for insulin secretion [58] |
| RIP-MyrAkt1 | C57/BL6 | Insulinoma | β-cell specific expression of constitutively active Myr-Akt leads to formation of insulinomas in S6K1 (a mTOR downstream target) dependent manner [59] |
| Avp-Tag | C57B1/10; CBA/J | Insulinoma | Mice bearing vasopressin promoter (1.2 kb 5′ sequence)-SV40 hybrid transgene uncharacteristically transformed pancreatic β-cells and anterior pituitary cells with no effect in hypothalamus and other organs where vasopressin is normally expressed [60] |
| Men1 TSM/+ | NIH Black Swiss; 129/Sv | Insulinoma | Mutation of one Men1 allele by homologous recombination leads to insulinoma development by 9 months and other tumors involving parathyroid, thyroid, adrenal cortex, and pituitary by 16 months mimicking human MEN1 syndrome [61] |
| Men1 +/T | 129 | Insulinoma and glucagonoma that dedifferentiated into advanced NF-pNETs | Disruption of one Men1 allele by gene targeting resulted in tumors of pancreatic, parathyroid, thyroid, pituitary, and adrenal glands exhibiting multistage progression and metastatic potential [62] |
| Men1f/f; RIP-Cre | C57BL/6 | Insulinoma | RIP-Cre mediated conditional knockout of Men1 gene leads to insulinomas and pituitary prolactinomas by 9 months [63] |
| Men1f/f; Glu-Cre | Not specified | Insulinoma | Surprisingly, loss of Men1 in α-cells resulted in β-cell insulinomas rather than glucagonomas suggesting the role of intercellular talk between islet cells [64] |
| Men1f/f; Pdx1-Cre | FVB; 129Sv | Insulinoma | Although Men1 is lost in both pancreatic exocrine and endocrine cells, only endocrine cells developed into highly angiogenic tumors suggesting the role of tissue-specific menin modulators and surrounding microenvironment during tumorigenesis [65] |
| Men1f/f; RIP2-CreER | 129; (C57BL/6 X CBA) | Insulinoma | Temporally controlled β-cell specific loss of Men1 led to insulinomas. Moreover, the model helps elucidate early stage events such as β-cell hyperproliferation [66]. |
| Men1f/f; RIP-Cre | B6; FVB; 129Sv | Insulinoma | Conditional knockout of both Men1 alleles promoted islet cell tumor development much faster than that of one allele [67] |
| Men1f/f; RIP-Cre | 129 | Insulinoma | Disruption of Men1 gene directly in β-cells led to insulinoma development by 6 months in a multistage fashion, exhibiting angiogenesis and altered E-cadherin and β-catenin expression [68] |
| Men1f/f; Glu-Cre | 129; B6/CBAJ-F1 | Insulinoma, glucagonoma, and mixed islet cell tumor | α-cell specific loss of Men1 leads to α-cell hyperplasia that grow into glucagonomas, however, majority of the hyperplastic α-cells transdifferentiate into insulinomas and mixed islet tumors [69] |
| Glu2-Tag | C57BL/6 | Glucagonoma | Expression of Tag under preproglucagon promoter drives hyperproliferation of alpha cells and formation of glucagonomas by 9–12 months. Promiscuous expression of T-antigen in hind brain neurons is not sufficient for their hyperplasia or tumorigenesis [70]. |
| Gcgr −/− | DBA/1 | Glucagonoma | Inhibition of glucagon signaling by glucagon receptor mutation causes α-cell hyperplasia that progress into islet dysplasia and solid tumors. A few animals develop mixed tumors or NF-pNETs [71]. |
| Pc2 −/− | C57BL/6 | Glucagonoma | Loss of prohormone convertase 2 required for glucagon synthesis leads to α-cell hyperplasia that develop glucagonomas and mixed islet tumors by 6–8 months [72] |
| RIP7-rtTA; tet-o-MT; p48-Cre; Ink4a/Arf f/f | C57BL6; FVB; ICR | Not determined | Loss of Ink4a/Arf tumor suppressor locus cooperates with overexpression of PyMT in pancreatic progenitor cells to induce pNET formation however at low incidence rate of 20% [73] |
| RIP7-rtTA; tet-o-MT; p48-Cre; Trp53f/f; Ink4a/Arf f/f | C57BL6; FVB; ICR | Not determined | Overexpression of oncogenic PyMT in β-cells together with deletion of P53 and Ink4a/Arf loci results in pNET incidence in 40% mutant mice [73] |
| pIns-c-MycERTAM/RIP-Bcl-xL | CBAxC57BL/6 | Insulinoma | Conditional expression of transgenic Myc and Bcl-xL to suppress Myc-induced apoptosis in islet β cells causes islet tumor development in a reversible fashion [74] |
| Pdx1-Cre; Trp53R172H;Rbf/f | FVB/N; J1; | Well differentiated, metastatic insulinoma and glucagonoma | Pancreas-specific p53 mutation and Rb deletion caused islet dysplasia that progressed to indolent and metastatic pNET in stepwise fashion [75] |
| Men1f/f Rb1f/f RIP-Cre; Men1f/f Ptenf/f RIP-Cre; Trp53f/f Rb1f/f RIP-Cre; | Men1f/f (129S, FVB) Rb1f/f(FVB;129) Ptenf/f(C;129S4) Trp53f/f(B6.129P2) RIP-Cre (C57BL/6) | Well differentiated G1, G2, and G3 pNETs (insulinoma) | Demonstrated the cooperative role of tumor suppressor genes, Men1, Rb1, Pten, and Trp53 in pNET suppression [76] |
| RIP-Tag2; Rabl6m/m | C57BL/6N | Insulinoma | Loss of oncogenic RABL6A attenuates pNET progression and angiogenesis in RIP-Tag2 mice [77] |
| Pdx1-Cre; Men1f/f; B7x KO | C57BL/6 | Insulinoma | Loss of B7x, an immune-checkpoint ligand, reduces islet β-cell proliferation and pNET formation consistent with increased T-cell infiltration [78] |
(Abbreviations: RIP = rat insulin promoter, MIP = mouse insulin promoter, Tag = T-antigen).