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. 2020 Jul 14;10:11581. doi: 10.1038/s41598-020-68507-z

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Hypothesised model of canine insulinomas tumour progression. We hypothesise two major changes occur during canine INS oncogenesis towards malignant progression. Early change: upregulation of beta-cell differentiation increases cell proliferation in the normal islets. Then dysregulation of membrane polarisation of cells disrupts the normal insulin homeostasis. Downregulation of Smad-signalling and pyruvate kinase activity further dysregulate the glucose-dependent insulin production. Increased numbers of islet cells and elevated insulin secretion induce a stressful microenvironment that cause trans differentiation of non-beta cells to beta-cells. In this scenario, cell–cell interactions diminish and cells acquire invasive capability. Late change: cell growth in the absence of cell–cell interaction causes loss of their cell adhesion and increase in the extracellular matrix remodelling to facilitate migration towards the lymphatic vessel. An increased cell survival mechanism (PI3K signalling) and increased inflammation (chemokine signalling) push the cells to disrupt the lymphatic vessel and metastasise to the adjacent lymph nodes. These mechanisms together might be responsible for promoting metastatic spread in INS.