Epithelial cancers in the post-genomic era: should we reconsider our lifestyle?

Abstract

The age-related epithelial cancers of the breast, colorectum and prostate are the most prevalent and are increasing in our aging populations. Epithelial cells turnover rapidly and mutations naturally accumulate throughout life. Most epithelial cancers arise from this normal mutation rate. All elderly individuals will harbour many cells with the requisite mutations and most will develop occult neoplastic lesions. Although essential for initiation, these mutations are not sufficient for the progression of cancer to a life-threatening disease. This progression appears to be dependent on context: the tissue ecosystem within individuals and lifestyle exposures across populations of individuals. Together, this implies that the seeds may be plentiful but they only germinate in the right soil. The incidence of these cancers is much lower in Eastern countries but is increasing with Westernisation and increases more acutely in migrants to the West. A Western lifestyle is strongly associated with perturbed metabolism, as evidenced by the epidemics of obesity and diabetes: this may also provide the setting enabling the progression of epithelial cancers. Epidemiology has indicated that metabolic biomarkers are prospectively associated with cancer incidence and prognosis. Furthermore, within cancer research, there has been a rediscovery that a switch in cell metabolism is critical for cancer progression but this is set within the metabolic status of the host. The seed may only germinate if the soil is fertile. This perspective brings together the different avenues of investigation implicating the role that metabolism may play within the context of post-genomic concepts of cancer.

Fig. 1

Epithelial cells in tissues with relatively high cell turnover accrue a large number of mutations by the time individuals reach their 6th or 7th decade. Elderly subjects harbour many epithelial cells with the number of mutations sufficient to induce malignant transformation. Most elderly individuals will as a consequence develop latent, occult neoplastic growths. In a normal lifespan, relatively few of these growths develop sufficiently to become clinically apparent cancers, and even fewer progress to invasive disease: the tip of a very large ‘iceberg’ of hidden cells with a malignant genome

Fig. 2

For most of the common epithelial cancers, there are decades between the occurrence of the initiating mutations and the appearance of a carcinoma. For individuals in their 60s or 70s, there are age-related declines in hormones reducing the drive for the progression of the neoplastic lesions that occur naturally with aging. The progression of these occult cancers is sufficiently slow such that within the normal lifespan of most subjects clinical disease does not have time to develop. With lifestyle-induced disturbances to metabolic control and the consequent hormonal imbalance, these occult tumours receive signals that the host organism is in a ‘fed state’ and in the transformed cells this can activate developmental programs promoting progression. In addition, these malignant cells are provided with a fertile soil in which to develop. The process can then be accelerated such that more of the occult cancers progress to develop clinical disease

Fig. 3

Within populations of humans there is considerable genetic heterogeneity between individuals. Within every individual, all of the somatic cells have an identical single genome but the cells develop considerable phenotypic heterogeneity: cells of the bone, skin, liver, nervous system, and immune system can have extremely different appearance and functions despite all being genetically identical. Within a tumour, the cells can acquire considerable genetic heterogeneity and a breast, prostate, or colorectal tumour in one patient can be genetically very different from that in another patient, partly because of the underlying somatic variations between individuals. Despite this considerable genetic diversity, tumours in the same tissue can manifest similar phenotypes

Fig. 4

a The PI3K pathway is the evolutionary conserved signalling pathway to ensure that growth and development is synchronised to the appropriate metabolic conditions: energy and substrate requiring processes only proceed when a ‘fed state’ is indicated. In metazoans, the insulin/IGF receptor modulates the activity of the PI3K pathway according to social signals indicating metabolic status throughout the organism. Growth and development is regulated, along with nutrient partitioning, and appropriate signals from the extracellular matrix (ECM) that are integrated via integrin receptors that associate with the insulin/IGF receptors in the cell membrane. b Perturbed metabolism and insulin/IGF activity can reprogram cell behaviour via modifying FOXO transcription factors: promoting epithelial mesenchymal transition and activating developmental cell programs resulting in cells adopting a metastatic phenotype. Mutations in the PI3K pathway and loss of PTEN can result in constitutive activation of the pathway promoting more autonomous control, less dependent on external signals, and further promotes progression and metastasis

Fig. 5

a A pre-industrialisation lifestyle, that is still prevalent in some Eastern societies, is associated with limited nutritional intake and high-energy expenditure. Metabolism is then maintained in balance as apparent by the low rates of metabolic disorders, such as obesity and diabetes, in such societies. With aging, oncogenic mutations naturally accrue in rapidly dividing epithelial tissues and as a consequence occult cancers appear; but with metabolism in balance the ‘soil’ is not fertile and the ‘seeds’ are not stimulated by endocrine signals and do not progress to clinical disease. The latent oncogenic potential still accumulates with aging but like the bulk of an iceberg it remains submerged. b The adoption of a Westernised lifestyle with excess nutritional intake and a sedentary lifestyle results in energy-imbalance perturbing metabolic control as reflected by the increasing prevalence of obesity and diabetes. This alters the internal ecosystem within the body such that the naturally occurring occult cancers are given signals to progress, that together with a more fertile ‘soil’, results in more of them developing to clinical cancers. c When the adoption of a Western lifestyle is combined with the control of life-shortening conditions then there is a shift in demographics with more of the population living longer into old age. This has exacerbated the prevalence of clinical cancers as the occult cancers, exposed to perturbed metabolic signals, have even longer to progress to clinical disease. The large burden of oncogenic potential that naturally accumulates with age then emerges as an epidemic of epithelial cancers: as the tip of this ‘iceberg’ becomes even more exposed