From Cell-Centric to System-Centric Carcinogenesis: The Repair and Capacity Adaptation (RCA) Conceptual Framework

This preprint presents the Repair and Capacity Adaptation (RCA) Conceptual Framework, a systems-biology model that explains carcinogenesis as a failure of progenitor-cell maturation within a degraded connective-tissue microenvironment. Whereas the Somatic Mutation Theory (SMT) defines cancer as a stochastic, cell-autonomous process driven by sequential genetic hits, quantitative analysis shows that such multi-hit events are statistically incompatible with realistic lineage lifespans. Experimental studies further demonstrate that malignant phenotypes can revert in normal tissue contexts, indicating that phenotype is controlled by environment rather than genome.

The RCA framework unites these findings by describing cancer as a systemic disorder of repair and differentiation control. When the fibroblast-derived Reticular Lamina (ReL) loses mechanical and biochemical integrity, differentiation cues collapse and proliferative progenitors become trapped in an immature, self-replicating state. This mechanism generalizes across organs—from prostate and epithelium to muscle, brain, and bone marrow—linking cancer, fibrosis, and degeneration as expressions of the same regulatory failure.

This work builds upon our previously published quantitative analysis of SMT limits (Olsen & Liisberg, 2025a, bioRxiv 10.1101/2025.10.17.683033) and forms Part II of the series From Cell-Centric to System-Centric Carcinogenesis.

Keywords: cancer systems biology; progenitor cells; extracellular matrix; differentiation arrest; RCA framework; somatic mutation theory; prostate cancer; regenerative oncology