Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue-Going Beyond Apoptosis Induction

Abstract

The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia.

Keywords: anakoinosis; communicative reprogramming; master modifiers; metastatic tumors; reprogramming information flux; systems biology.

Figure 1

Four major communication tools for inducing anakoinosis: Changing flux of information. Concertedly, oncogenic events and “recessively” developing disease traits constitute the tumor phenotype, which is communication-technically mediated by the tumor's “background knowledge.” Clinical data on pro-anakoinotic therapy approaches indicate successful therapeutic modeling of homeostatic processes, including distant organ sites. Pro-anakoinotic therapies with their regulatory activity profile may sideline classic tumor-promoting pathways or cells with oncogenic load by activating alternative communication flux. Thus, pro-apoptotic pathways may be re-activated, or tumors may be kept in check. The observed communication-technical functional reset of the tumors' heterologous cell compartments reveals a set of general communication rules, which are accessible for a broad diversity of biomodulatory interventions. Biologic tumor features, which are communication-technically accessible, are severely dysregulated transcriptional programs, homeostatic pathways, immune responses and down-regulated tumor suppressor genes, respectively. (A) The sum of extrinsically, i.e., therapeutically, and intrinsically inducible evolutionary processes within the tumor environment (tumor stroma, hosting organ, distant organ sites). (B) Modular events: Changing validity (availability on demand at distinct time points) and denotation (current functional impact at a distinct systems stage of systems objects. (C) Communicative interactions of the tumor with tumor hosting organ and the organism for generating novel functions, structures and hubs, thereby defining cell identity. (D) Hallmarks of cancer are differentially physically realized and constitute normative notions; are to some degree histology- and genotype-independent; may be re-directed and reorganized by anakoinosis.

Figure 2

Reprogramming hallmarks of cancer via dysregulated homeostatic pathways and non-oncogene addictions. Tumor cells with diverse clusters of cancer signature genes generate in close interaction with adjacent stroma cells hallmarks of cancer via distinct physical constitutions of these hallmarks. Communication-technically described, the physical constitutions of hallmarks operate modules comprising master regulator proteins for maintaining combined with stroma cells the tumor cell state. Pro-anakoinotic therapies demonstrate that targeting patterns of non-oncogene addicted targets with combinations of master modifiers, may specifically change the communicative context, namely validity and denotation of systems participators, and finally, induce tumor response. Importantly, in contrast to multifold genetic clusters constituting unique hallmarks, for example rapidly displacing growth, these clusters might support only a restricted amount of constitutions for characteristic cancer hallmarks.

Figure 3

Resetting information flux in tumor disease. Multifold possibilities for resetting information flux in tumors with master modifiers for establishing long-term tumor control in metastatic resistant disease.

Figure 4

Reverse anakoinosis, i.e., induction of oncogenic events via concerted activity of as single substances non-oncogenic agents.

Figure 5

For therapeutic considerations, cancer is currently considered as a cell-autonomous disease. Successful administration of anakoinosis inducing therapies indicates that neoplastic cells are also non-cell autonomous: Targeting homeostatic pathways and “normalizing” their dysregulation in neoplastic tissue may be sufficient for inducing long-term response, even continuous complete remission. TME, tumor microenvironment; CAF, cancer-associated fibroblasts; DC, dendritic cells; TAM, tumor-associated macrophages; NK, natural killer cells; Treg, regulatory T-cells; Tc, T cells; MDSC, myeloid-derived suppressor cells.