These potential insulin-induced epigenetic changes would functionally mimic both a (preceding) growth-promoting effect of an insulin-RB complex formation and a (subsequent) gene mutation pattern that may arise during the further evolution of these cells/tissues towards malignancy. In other words, the viral oncoprotein-like insulin molecule [27, 31] would display two distinct properties that are functionally equivalent in terms of driving oncogenesis [18]. Moreover, the immunohistochemical identification of insulin in lung cancer tissue samples (whereby, besides the actual tumor cells, some normal pneumocytes were also revealed to be insulin-positive)

in see more the absence of detectable insulin Mizoribine datasheet transcripts [32] additionally strengthens the concept of a pathological spread of (blood-borne) insulin in malignant diseases.

Beyond insulin, there are also other candidate molecules that could undergo an oncoprotein metastasis, e.g. osteopontin. Accordingly, it has been shown that osteopontin is found in premalignant and malignant cells derived from patients with tumors of the oral cavity [33] and, moreover, that osteopontin translocates to the nuclei of mitotic cells [34]. Entirely consistent with the oncoprotein metastasis concept and intriguingly, it has furthermore been shown that primary tumor-derived and blood-borne osteopontin is able to promote the microenvironmental changes necessary for

distant metastatic seeds [35]. Most Edoxaban recently, a known amino acid labeling technique has been extended to investigate intercellular communication via both secreted and internalized proteins such as metastasis associated protein 3 and retinoblastoma binding protein 7 [36]. It will therefore be interesting to probe in future studies as to whether these proteins can add to insulin and osteopontin as mediators of the proposed oncoprotein metastasis phenomenon. Since it thus appears that that there are various proteins that cross subcellular borders and thereby contribute to carcinogenesis, a therapeutic strategy that suggests itself in order to counteract these microbial infection-like, transcellular processes of malignancy would be to administer cell-permeable agents that directly block these mobile oncoproteins. Possible pharmacological candidates for such intervention are cell-penetrating tumor suppressor peptides, in particular those targeting the RB and nucleocrine pathways [17, 18, 28, 30, 37–40]. In this context, a parallel is noteworthy: in the same way as insulin’s internalization into cells is not saturable [41] nor is that of a 16-amino acid fragment derived from the Antennapedia SIS3 molecular weight homeodomain and termed “”Penetratin”" either [42].