High vimentin expression with E-cadherin expression loss predicts a poor prognosis after resection of grade 1 and 2 pancreatic neuroendocrine tumors

Zhou, Bo; Xiang, Jie; Jin, Ming; Zheng, Xiang; Yan, Sheng

doi:10.1186/s12885-021-08062-6

Cited by 14 publications

(10 citation statements)

References 29 publications

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“…Finally, not only does PKD1 signaling promote metastatic potential by upregulating expression of vimentin and increasing the number of ALDH1 + CSCs [ 87 , 88 , 89 ], this pathway may also increase the expression of CD36 to activate fatty acid metabolism and further enhance metastatic potential [ 62 ]. Therefore, identification of the PKD1 pathway in CSC plasticity with a partial EMT phenotype may provide new insights into CSC biology in a variety of cancer types, since EMT is important during the metastatic stage, while E-cadherin-induced MET facilitates subsequent colonization [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity

Guo

Jiang

Rose

et al. 2022

Cells

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Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity

Guo

Jiang

Rose

et al. 2022

Cells

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“…In addition, not only does PKD-1 signaling promote metastatic potential by upregulating expression of vimentin and increasing the number of ALDH1 + CSCs [81][82][83], this signaling also increases the expression of CD36 to activate fatty acid metabolism and further enhances metastatic potential [57]. Therefore, identification of the PKD-1 pathway in CSC plasticity with a partial EMT phenotype may provide new insight into CSC biology in a variety of cancer types since EMT is important during the metastatic stage while E-cadherin-induced MET will aid in the subsequent colonization [29,30].…”

Section: Discussionmentioning

confidence: 99%

PKD-1 Signaling Is Required for the Maintenance of CSCs with Epithelial-mesenchymal Plasticity in Pancreatic Neuroendocrine Tumors

Guo

Jiang

Rose

et al. 2022

Preprint

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Pancreatic neuroendocrine tumors (pNETs) are extremely heterogeneous and highly vascularized neoplasms that arise from endocrine cells in the pancreas. pNETs harbor a subpopulation of stem cell-like cancer cells (cancer stem cells/CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study we demonstrated that CSCs in human pNETs co-expressed PKD-1 and CD44. We further identified PKD-1 signaling as a critical pathway in the regulation of CSC maintenance in pNET cells. PKD-1 signaling regulated the expression of a CSC-related gene signature and promoted CSC self-renewal. Intriguingly, pharmacological or genetic disruption of PKD-1 signaling in human pNET cells impaired lysophosphatidic acid-induced expression of genes associated with epithelial to mesenchymal transition (EMT), specifically E-cadherin and vimentin. This study indicates that PKD-1 signaling is essential for the maintenance of a subpopulation of CSCs in pNETs at an intermediate state along the epithelial to mesenchymal spectrum, thereby leading to a CSC phenotype with plasticity and partial EMT. Inhibiting the PKD-1 pathway may facilitate the elimination of CSC subpopulations to curb pNET progression, therapeutic resistance and metastasis. Given that the signaling networks associated with CSC maintenance and EMT are complex and extend across multiple levels of gene regulation, this study provides insight into signaling regulation of partial EMT in determining CSC fate and aids in developing potential therapeutic strategies that target different subsets of CSCs in a variety of cancers.

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“…Less is known about vimentin in NENs. In a study of patients with Grade 1 and 2 NENs, approximately 25% tumour tissues expressed vimentin [ 40 ]. Our data showed that three out of the four G3 tumours had lower vimentin relative to that in non-tumour than the G2 tissue did.…”

Section: Discussionmentioning

confidence: 99%

EMT Molecular Signatures of Pancreatic Neuroendocrine Neoplasms

Venugopal

Michalczyk

Khasraw

et al. 2022

IJMS

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Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA and synaptophysin and the proliferation marker Ki-67 are used. These parameters, however, are qualitative and lack the capacity to fully define the tumour phenotype. Molecules of epithelial–mesenchymal transition (EMT) are potential candidates for improved tumour characterisation. Using qRT-PCR, we measured mRNA levels of 27 tumour markers, including 25 EMT-associated markers, in tumour tissue and matched non-tumour tissues for 13 patients with pancreatic NENs. Tissue from patients with three different grades of tumour had distinctly different mRNA profiles. Of the 25 EMT-associated markers analysed, 17 were higher in G3 tissue relative to matched non-tumour tissue, including CD14, CD24, CD31, CD44, CD45, CD56, CK6, CK7, CK13, CK20, NSE, CDX2, CgA, DAXX, PCNA, laminin and Ki-67. The differences in levels of seven EMT-associated markers, Ki-67, DAXX, CD24, CD44, vimentin, laminin and PDX1 plus CgA and NSE (neuroendocrine markers) enabled a distinct molecular signature for each tumour grade to be generated. EMT molecules differentially expressed in three tumour grades have potential for use in tumour stratification and prognostication and as therapeutic targets for treatment of neuroendocrine cancers, following validation with additional samples.

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High vimentin expression with E-cadherin expression loss predicts a poor prognosis after resection of grade 1 and 2 pancreatic neuroendocrine tumors

Cited by 14 publications

References 29 publications

Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity

Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity

PKD-1 Signaling Is Required for the Maintenance of CSCs with Epithelial-mesenchymal Plasticity in Pancreatic Neuroendocrine Tumors

EMT Molecular Signatures of Pancreatic Neuroendocrine Neoplasms

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