Epistemology of the origin of cancer: a new paradigm

Abstract

BackgroundCarcinogenesis is widely thought to originate from somatic mutations and an inhibition of growth suppressors, followed by cell proliferation, tissue invasion, and risk of metastasis. Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers. Those remaining, 70 to 80%, are called “sporadic,” because they are essentially of unknown etiology. We propose a new paradigm for the origin of the majority of cancers.Presentation of hypothesisOur paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. If we are correct, this paradigm would suggest that the majority of the findings in cancer genetics so far reported are either late events or are epiphenomena that occur after the appearance of the pre-cancerous niche.Testing the hypothesisIf, based on experimental and clinical findings presented here, this hypothesis is plausible, then the majority of findings in the genetics of cancer so far reported in the literature are late events or epiphenomena that could have occurred after the development of a PCN. Our model would make clear the need to establish preventive measures long before a cancer becomes clinically apparent. Future research should focus on the intermediate steps of our proposed sequence of events, which will enhance our understanding of the nature of carcinogenesis. Findings on inflammation and fibrosis would be given their warranted importance, with research in anticancer therapies focusing on suppressing the PCN state with very early intervention to detect and quantify any subclinical inflammatory change and to treat all levels of chronic inflammation and prevent fibrotic changes, and so avoid the transition from a normal cell to a cancer cell.Implication of the hypothesisThe paradigm proposed here, if proven, spells out a sequence of steps, one or more of which could be interdicted or modulated early in carcinogenesis to prevent or, at a minimum, slow down the progression of many cancers.

Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

“…“Cancer is a complex and heterogeneous set of diseases with no simple definition” [2,106]. The orchestration of cell-cell communication during carcinogenesis is not well understood as it encompasses different feedback loops and both activating and inhibiting paths of different forms of communication, as well as a fine-tuning mechanism and disarrangement.…”

“…“Biological processes as well as cell-cell communication and signaling are themselves a multidimensional musical opera in different acts, which are played differently by different symphony orchestras rather than by a soloist. Even the composition of the music, which is needed before it can be played, is still not well understood.” [2]. Achievements in anticancer therapy and as yet unmet opportunities, including the proposal for new anticancer strategies, have recently been reviewed [3].…”

“…His theory, although widely touted, remains unproven; and it is the source of a flawed paradigm. Mutations are most likely later events, or epiphenomena, in a multistep sequence of events through which the majority of cancers originate [2]. An understanding of cell-cell communication is important to understanding these sequential events that lead to a cancer.…”

Science belongs to no one—and to everyone

“…Enduring curiosity is needed to find answers and to question the existing paradigms (especially the selfgenerated ones). A Danish patient-cohort study on 445,456 patients revealed, for example, that patients with diverticulitis, when compared to healthy controls, have double the risk of cancer [22], an elevation that could be attributed to chronic inflammation [23]. Resection of the sigmoid, after the second event of sigmoid diverticulitis, eliminates this risk.…”

Molecular aspects of breast cancer resistance to drugs (Review)

“…The alteration of the ECM changes promote the formation of a tumorigenic microenvironment, stimulating angiogenesis through angiogenic factors like VEGF, which determines the beginning of the vascular branches and facilitates metastasis of tumor cells, with infiltration of immune cells and progression of the cancer (64). A sequence of processes, including transition of normal to cancerous cells and later events such as proliferation, migration, invasion, mutations, and angiogenesis have been reported (65). All these steps accompanied by pathogenic stimuli, chronic inflammation, fibrosis, formation of precancerous niches, help the cells escape chronic stress.…”