Somatic mutation theory versus tissue-level (microenvironment) views of cancer
The somatic mutation theory (SMT) explains cancer as the result of accumulated DNA mutations in a single somatic cell.4 The tissue organization field theory (TOFT) instead treats cancer as a problem of tissue organization.6 The two views differ on the level at which cancer begins. That difference bears on how experiments are modelled and how treatments are judged.12
- Earliest held
- 2014, Bizzarri M, Cucina A
- Most discussed in
- Bioelectric Dysregulation in Cancer…, 2022
- In the library
- 37 passages in 11 works
- Rewritten
- 2026-10-21
The mutation view
Sheth and Esfandiari (2022) describe SMT as the prevailing theory in cancer research for more than sixty years.4 In their account, tumor development is a multistep process in which successive mutations give advantages. They credit SMT with explaining hereditary cancers and the success of gene-targeting therapies.4 Bizzarri and Cucina (2014) state the claim at the level of the cell. In their reading, SMT places cancer at the cellular and subcellular level and treats it as a failure of control over proliferation and invasiveness, caused by mutations or overexpression of a class of genes.1
Objections and the field theory
Bizzarri and Cucina argued that therapies built on SMT have been ineffective in clinical management.2 They said SMT yielded a large body of data on gene and protein networks, but also an impasse, because more results contradict its premises.2 Sheth and Esfandiari pointed to two such results: carcinogens that act without DNA modification, and tumors with no mutations.5 They date TOFT to 1999 and describe it as locating carcinogenesis in tissue organization.6 Bizzarri and Cucina describe the microenvironment in TOFT as the physical and biochemical support of a morphogenetic field that steers epithelial cells.3
Microenvironment and bioelectric work
Levin is a co-author of later papers by Masuelli and colleagues on tumor-microenvironment crosstalk. Masuelli and colleagues (2022) reported that left and right breast tumors differ consistently in incidence, gene expression and DNA methylation. They postulated that different tumor-microenvironment crosstalk on each side produces different tumorigenesis mechanisms.7 Masuelli and colleagues (2023) discussed ion channels in this setting. They wrote that channels on cancer cells can sense changes in pH, oxygen tension and ion concentration in the microenvironment, and that this alters signalling and gene expression.8
An atavistic alternative
Pio-Lopez and Levin (2026) describe SMT as an account of cancer through sequential mutations and natural selection within the body, citing Soto and Sonnenschein (2004).9 They set against it the atavistic model. This model holds that ancient functions of early and unicellular life are involved in the disease.9 They list uncontrolled growth, lack of response to growth inhibitors and increased stress tolerance. They also report that phylostratigraphic analysis has dated many cancer-associated genes to the rise of unicellular life, eukaryotes or multicellularity.9
SMT explains cancer as a process taking place at the cellular/subcellular level of biological organization and claims that cancer is a problem of regulatory control of cell proliferation and of invasiveness
Bizzarri M, Cucina A, 2014 · Tumor and the microenvironment: a chance to reframe the paradigm of… · open at passage 5Yet, current therapeutic approaches based on that paradigm have been proven to be ineffective in clinical cancer management
Bizzarri M, Cucina A, 2014 · Tumor and the microenvironment: a chance to reframe the paradigm of… · open at passage 5According to TOFT, the microenvironment represents the physical-biochemical support of the morphogenetic field which drives epithelial cells towards differentiation and phenotype transformation
Bizzarri M, Cucina A, 2014 · Tumor and the microenvironment: a chance to reframe the paradigm of… · open at passage 6The somatic mutation theory (SMT), which has been prevailing in cancer research for more than sixty years proposes that the origin of cancer can be explained by an accumulation of several DNA mutations in a single somatic cell.
Sheth M, Esfandiari L, 2022 · Bioelectric Dysregulation in Cancer Initiation, Promotion, and Progression · open at passage 2However, non-genotoxic carcinogens which induce cancer without any DNA modifications (3) and the absence of mutations in some tumors (4) contradict this theory.
Sheth M, Esfandiari L, 2022 · Bioelectric Dysregulation in Cancer Initiation, Promotion, and Progression · open at passage 2the tissue organization field theory (TOFT) proposed in 1999, hypothesizes that carcinogenesis is a problem of tissue organization instead of having a cellular level origin.
Sheth M, Esfandiari L, 2022 · Bioelectric Dysregulation in Cancer Initiation, Promotion, and Progression · open at passage 2L/R-sided breast tumors exhibit consistently-biased incidence, gene expression, and DNA methylation. We postulate that a differential L/R tumor-microenvironment crosstalk generates different tumorigenesis mechanisms.
Masuelli S, Real S, Campoy E, Branham MT, Marzese DM…, 2022 · When left does not seem right: epigenetic and bioelectric differences between… · open at passage 0ICH expressed by cancer cells can sense and respond to changes in the TME, such as alterations in pH, oxygen tension, and ion concentration, leading to changes in intracellular signaling and gene expression
Masuelli S, Real S, McMillen P, Oudin M, Levin M, Roqué M, 2023 · The Yin and Yang of Breast Cancer: Ion Channels as Determinants of Left-Right… · open at passage 2the atavistic model is based on the idea that ancient functionalities that were essential for early and unicellular life forms are involved in the disease.
Pio-Lopez L, Levin M, 2026 · Atavistic Genetic Expression Dissociation (AGED) During Aging… · open at passage 40