Cancer - as chronic low-grade sterile inflammation of somatic cells

How does Cancer form? The current mainstream concept is the somatic mutation theory (SMT). Normal cells gradually accumulate mutations due to DNA replication errors, cellular stress, and mutagen exposure. Inspired by the neo-Darwinian view of evolution, those cells gain proliferative advantages and progressively expand in the population. Because those mutations always happen in a single cell, the progeny of the single cell that gained those mutations forms clonal populations. Malignancy has been considered the extension of this selection process. Gaining the ability of invasion, metastasis and evasion from immune surveillance is considered as advantageous. Malignant cells get clever and unbeatable. The search for the mutations driving tumorigenesis and malignancy, i.e. metastatic genes, has been conducted for the last decades. On the other hand, it has been recognized that aged individuals carry various oncogenic mutations in morphologically normal tissues with clonal growth, suggesting oncogenic mutations are insufficient for carcinogenesis. In addition, the importance of the tumour microenvironment in cancer initiation, progression and drug resistance has been appreciated. The series of new data challenges the simplistic view of the SMT and calls for significant revisions in the mechanisms of carcinogenesis. Virchow and Dvorak phrased cancer as “a wound that does not heal” a century ago—disorganization and signs of inflammation. Malignant cells appear the low-grade chronic sterile inflammatory condition of somatic cells. The low-grade chronic sterile inflammatory epithelial cells engage adjacent tissue residential macrophages (TRMs) that can remodel ECMs, similar to wound healing. ECM remodelling stimulates the entry of the cell cycle of the epithelial cells, similar to tissue dissociation. Most adult cells can enter the cell cycle despite being quiescent in vivo when dissociated and placed in tissue/organoid culture conditions, suggesting in vivo 3D tissue structures suppressing cell-cycle entry. Then, how does a cell gain intrinsic inflammation activity without pathogens? Dysregulation of nucleic acid localization and syntheses like cytosolic DNA and R-loops due to cell-cycle entry under stress conditions falsely activates intrinsic innate viral sensing systems to initiate sterile inflammation. We hypothesize that gaining false activations of innate viral sensing systems in somatic cells is the first step of malignancy initiating TME formation.Chronic low-grade sterile inflammation in somatic epithelial cells permits communication with their surrounding cells, primarily tissue residential macrophages (TRMs), and forces their engagements- the emergence of TME. Here are the two aims of this proposal: Aim 1: Investigating the importance of the false activation of the innate viral sensing mechanism, the cGAS/STING pathway, in malignancy initiation. Aim2: Investigating the development of tumour microenvironment from normal microenvironment – involvement of tissue-resident macrophages and pericytes. We consider that malignancy is not the individual cellular property but the consequential state of communication circuits between the cancer cells and surrounding cells. We hope that the concept of simultaneous double/triple perturbations against multiple interconnected circuits should emerge in cancer treatments.

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