The reason why a genuine therapeutic breakthrough remains as yet unachieved [8] could likely be that our strategies CFTRinh-172 molecular weight to tackle cancer are still incompletely integrating the many pieces of the puzzle that we have already accumulated and the various concepts already advanced on the basis of this knowledge. In accordance with this interpretation, Richmond Prehn asked already in 1994 [9] the crucial hen-and-egg question on cancer pathogenesis as to what comes first: the cancer process per se or the mutations in genes pertaining

to morphologically overt cancer cells? This call for a possible paradigm shift remains a challenge until today, yet some key elements of such malignant process can be already found in the literature of the past two decades. Accordingly, it has been observed that the cancer process may begin very early, specifically at the level of the DNA structure in (morphologically) normal cells adjacent to primary tumors [10]. Furthermore, it was concluded that certain post-translational events that inactivate a given tumor suppressor protein could be regarded as functionally equivalent to an inactivating mutation of its gene, for instance retinoblastoma protein (RB)’s physical interaction with a viral oncoprotein or the former’s hyperphosphorylation [11]. Post-translational events such

as the increase in the stability of an oncoprotein were equally recognized as crucial for a pathologically accelerated cell cycle progression [12]. Moreover, it was found that hypermethylations in the promoters of genes BEZ235 supplier encoding growth-suppressive proteins check details often mimic the patterns for mutations in the respective genes [13]. Also, the phenomenon of nuclear exclusion of tumor suppressors through their cytoplasmic sequestration by distinct proteins has been recognized Thiamet G as another mechanism corresponding to an inactivating mutation of the respective tumor suppressor gene [14, 15]. In addition, protein-based inflammatory processes in the

tumor microenvironment are likely to influence the tumor cells embedded in that specific area [16]. The key twist common to these molecular insights is that the post-translational/epigenetic events they refer to may conceivably occur in morphologically normal cells that, moreover, have not yet acquired modifications in their growth-regulatory genes, yet these events might already constitute a (pre)malignant process that is ongoing in these seemingly normal cells. Oncoprotein metastasis disjoined: a reappraisal Several years ago, I have expanded this view by my concept on an oncoprotein metastasis (OPM) and its possible therapeutic reversal [17, 18]. In analogy to the possibilities of a transfer of disease from one organ site to another, i.e. of metastasis by means of a) microorganisms, e.g. bacteria [19], or b) cells, e.g.