ANAKOINOSIS

Anticancer therapies aim at killing cancer cells, thereby reducing tumor mass. Unfortunately, repopulation too often ensues, causing fatal relapses: cancer tissues wounded by cytotoxic or targeted therapies regenerate via the “phoenix rising” pathway that is mediated, counterintuitively, by the apoptotic cells themselves, which promote PGE2-dependent proliferation of cancer cells surviving the treatment (1). This seems to be an intrinsic limit of such therapies, calling for a change of paradigm: could cancer tissues, instead of cancer cells, be the target of therapeutic strategies aiming at tissue “re-education”? Anakoinosis, from the Grecian “communication”, is a paradigmatic new therapy (2) aiming at correcting aberrant cancer homeostasis re-activating lost tissue defences, e.g., epithelial polarity and classical tumor suppressors. Using compounds acting as “master modulators” of gene expression, without cytotoxic drugs, originally designed for palliative care, anakoinosis showed unexpected anticancer potential, reaching even clinical continuous complete remission of otherwise untreatable metastatic cancers. Strikingly, upon anakoinosis, cancer cells may re-acquire normal functions while maintaining an abnormal genetic pattern. Innovative techniques (e.g., 3D cell culture, lab-on-chip devices), revealing a more modern and complex view of cancer going beyond the mere oncogene mutations, provide solid scientific basis to explain the clinical achievements of anakoinosis. In particular, it is emerging that the continuous flux of information between different tissue entities, cells and matrices, modulates gene expression, promoting tumor-suppressive pathways absent in traditional 2D cultures lacking the correct architecture (3). Thus, epithelia can include, exploit, and keep in check, even cells with oncogene mutations (4), as shown by single-cell sequencing of normal tissues from elderly people (5). Cancer would thus only arise when tissues lose the homeostatic control on mutated cells; vice versa, bio-modulators may restore such controls, re-educating tissues for a durable cancer remission and long-term tumor control.

References
1. Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, Li CY. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci Signal. 2010 Feb 23;3(110):ra13. doi: 10.1126/scisignal.2000634
2. Heudobler D, Rechenmacher M, Lüke F, Vogelhuber M, Klobuch S, Thomas S, Pukrop T, Hackl C, Herr W, Ghibelli L, Gerner C, Reichle A. Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis.
3. Partanen JI, Tervonen TA, Myllynen M, Lind E, Imai M, Katajisto P, Dijkgraaf GJ, Kovanen PE, Mäkelä TP, Werb Z, Klefström J. Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):E388-97. doi: 10.1073/pnas.1120421109
4. Marques E, Peltola T, Kaski S, Klefström J. Phenotype-driven identification of epithelial signalling clusters. Sci Rep. 2018 Mar 5;8(1):4034. doi: 10.1038/s41598-018-22293-x
5. Martincorena I. Somatic mutation and clonal expansions in human tissues. Genome Med. 2019 May 28;11(1):35. doi: 10.1186/s13073-019-0648-4