Epithelial Cell Proliferation: Circadian Rhythms and Derangements in Cancer
All epithelial tissues continue to proliferate throughout life—indeed even for a time after death. This is an exquisitely controlled process, designed so that the adding of new cells is precisely balanced with the need for developing the tissue or organ in growth and development phases of life (from embryogenesis to adulthood); with the loss of mature cells through desquamation and apoptosis during adulthood to keep structures in a healthy mature state (homeostasis). As we age there is an inevitable imbalance, with atrophy and some loss of function. But if you don’t use it you lose it, and epithelia remain able to respond if functionally stimulated at any age. This applies to all tissues and organs, including the central nervous system, as is increasingly recognised: this applies to all epithelia, including solid organs like liver and pancreas, which retain renewal and regenerative capacity.
Here we are concerned with stratified squamous epithelia. Cell division in basal layers, cell movement, maturation and shedding are under precise control, with a recognised diurnal variation (Warnakulasuriya and MacDonald 1993) and with chemical signals from cells moving towards the surface instructing cells in the proliferation compartment to divide, depending on their position in the passage to the surface, and the thickness of the epithelium required. Abrasion or erosion triggers increased signal. This is best understood by the theory of control by cha- lones: leakage of these chemical messages stimulates cell division by a negative feedback loop. Chalones were first described by Bullough and Laurence (1968) in the 1960s and Elgjo and colleagues (2004), after a flurry of research activity in the 1970s, have returned to contention: the properties are now thought to be those of member(s) of the family of Growth Factors, the TGFp Superfamily (Elgjo and Reichelt 2004) which act through the Smad pathway.
Stimulatory factors include, in addition to TGFs: human epidermal growth factors (EGF); Interleukins -1 and -2 (IL-1, IL-2, IL-6); GM-CSF (colony stimulating factor); Basic FGF (fibroblast growth factor); keratinocyte growth factors (KGF); Vitamin A and associated retinoids; androgens. These all act by binding with specific receptors on the cell surface, amongst the most important of which are the EGFR/ERBb family. Drugs based on monoclonal antibodies designed to block EGFR, are now licenced for the treatment of HNSCC, the only true biotherapeutic currently licensed for treatment of HNSCC. Such approaches are the basis of personalised medicine: only HNSCC patients whose neoplasm over-expresses EGFR, and only those breast cancer patients whose neoplasm overexpresses HER2 receptors, will benefit from Cetuximab and Herceptin treatment, respectively. The current situation is described on detail in Chap. 6 by Schmitz and Machiels in this Volume.
Physiological inhibitors of keratinocyte proliferation include IFNa, IFNy, TNFa, adrenaline, glucocorticoids and high local calcium levels.
The multiple pathways of cell proliferation are reviewed by Feitelson et al. (2015) with particular emphasis on natural compounds which cause interference and have value as anticancer agents.