Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13927-31. doi: 10.1073/pnas.1312831110.

Promotion and selection by serum growth factors drive field cancerization, which is anticipated in vivo by type 2 diabetes and obesity.

Harry Rubin

Department of Molecular and Cell Biology

Life Sciences Addition, University of California, Berkeley, CA  94720-3200.  USA

Telephone:  510-642-6617

FAX:  510-643-6791

eMail: hrubin@berkeley.edu

Abstract

Individuals suffering from type 2 diabetes or obesity exhibit a significant increase in the incidence of various types of cancer. It is generally accepted that those conditions arise from overnutrition and a sedentary lifestyle, which lead to insulin resistance characterized by overproduction of insulin acting as a growth factor. There is a consensus based largely on epidemiological data that chronic overproduction of insulin is responsible for the increased incidence of cancer. A model system in culture of NIH 3T3 cells induces the collective effects of serum growth factors on progression through the stages of field cancerization. It shows that the driving force of progression is promotion of cell growth under selection at high cell density, with no requirement for exogenous carcinogenic agents. The early effect is gradual selection among many preexisting, low-penetrance preneoplastic mutations or stable epigenetic variants, followed by sporadic, high-penetrance transforming variants, all dependent on endogenous processes. The significance of the results for cancer in diabetic and obese individuals is that the initial stages of the process involve multiorgan metabolic interactions that produce a systemic insulin resistance with chronic overproduction of insulin and localized field cancerization. Hypomagnesemia is prevalent in the foregoing metabalo/systemic disorders, and may also provide a selective microenvironment for tumor development.

KEYWORDS: hyperinsulinemia, neoplastic transformation, preneoplasia

PMID: 23908399

 

Supplements: 

Two years ago I read in a News and Focus article that “obese and diabetic individuals have a far higher risk than lean and healthy people of getting cancer, and when they do get it, the risk of dying from it is greater”. (1) Although the relationship involves a variety of solid, epithelial cancers, the most complete studies have been in colorectal cancer.  It is widely thought that the increases in cancer are produced not by directly damaging DNA but by promoting the growth of cells.  This does not agree with the standard initiation/promotion scheme of carcinogenesis in which the initiating event is damage to DNA, which elicits mutations, and the secondary effect which promotes the growth of mutated cells.

The usual marker of tumorigenesis is the appearance of discrete nodules of proliferating cells.  However, there is evidence of a prolonged preneoplastic period of hyperplasia.  The hyperplastic fields were originally discovered as flat areas in the margins of surgically removed tumors.  These fields were thought to be the soil in which the tumors originate, but there was no way of studying this early phase of neoplastic development in humans, nor could their origin be quantitatively studied in experimental animals. Furthermore, no method could be systematically studied in cell culture.

That changed when a cell culture model was found that reproduced all phases of tumor development, beginning with the hyperplastic fields (2).  The discovery of these marginal fields had been made in sections of human cancer, and the entire process to tumor development was named field cancerization.  The cell culture model of field cancerization revealed that the early fields, like those of human cancers, arose not by carcinogens that damaged DNA but by promotion of proliferation driven by the collective effect of enhanced concentrations of normal growth factors in serum.  They could also account for the increased incidence of cancer in type 2 diabetes and obesity.  The main growth factor in these metabolic disorders was thought to be an increase of circulating insulin that often occurs in the process called insulin resistance.  The cell culture model showed that the hyperplastic fields resulted from selection of spontaneously mutated cells from a heterogeneous population that had a growth advantage at high cell density.  Repeated rounds of selection ultimately increased the saturation density of the cells by selecting the pre-existing mutations.  When the saturation densities reached a high level there appeared new mutations that could grow so well at high densities that they produced discrete, multilayered foci of neoplastic cells that could make tumors in animals.

It is now believed by many researchers that most, if not all, solid epithelial cancers in man arise through the process of field cancerization.  Therefore the cell culture model can be used to test for treatments that inhibit the development of cancer at the field stage.  Such inhibitions might inhibit the recurrence of tumors at sites of surgical excision.

An additional concern is the nature of the tumor environment that selects for cells that can grow at high densities.  A hint comes from the prevalence of magnesium deficiency in metabolic disorders.  Such a deficiency is bound to damage energy production particularly in fat, liver and muscle.  But neoplastic cells grow much better than normal cells in low magnesium (Fig. 1), (see ref. 3).  Therefore magnesium deficiency should select for preneoplastic cells and their progression to malignancy.  The cell culture model provides a means for testing this proposal.  If proven, it would suggest magnesium supplementation in out diets to inhibit the development of cancer, as it has improved the symptoms of type 2 diabetes (4).  Positive results would also indicate that carcinogenesis begins as a systemic process that precedes field cancerization. Therefore practices such as physical exercise and proper diet that minimize the effects of type 2 diabetes might also reduce the incidence of cancer (5).

 

References

1.         Taubes G (2012) Unraveling the obesity-cancer connection. Science 335:28-32.

2.         Rubin H (2011) Fields and field cancerization: The preneoplastic origins of cancer. BioEssays 33:224-231.

3.         Rubin H (1981) Growth regulation, reverse transformation, and adaptability of 3T3 cells in decreased Mg2+ concentration. Proc. Natl. Acad. Sci. USA 78:328-332.

4.         Paolisso G & Ravussin E (1997) Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium. Amer. J. Hypertension 10:346-355.

5.         Willett WC (2002) Balancing life-style and genomics research for disease prevention. Science 296:695-698.

 

Harry Rubin-1Fig. 1  Multiplication of normal (clone 2) and transformed (clone 14) cells in various concentrations of Mg2+.  The Mg2+ concentrations of the symbols for clone 14 are the same as the symbols shown for clone 2 (3).

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