Estrogen as an Essential Resource and the Coexistence of ER+ and ER– Cancer Cells

Abstract

Diagnosis of estrogen sensitivity in breast cancer is largely predicated on the ratio of ER+ and ER– cancer cells obtained from biopsies. Estrogen is a growth factor necessary for cell survival and division. It can also be thought of as an essential resource that can act in association with other nutrients, glucose, glutamine, fatty acids, amino acids, etc. All of these nutrients, collectively or individually, may limit the growth of the cancer cells (Liebig’s Law of the Minimum). Here we model estrogen susceptibility in breast cancer as a consumer-resource interaction: ER+ cells require both estrogen and glucose as essential resources, whereas ER– only require the general resource. The model predicts that when estrogen is the limiting factor, other nutrients may go unconsumed and available at higher levels, thus permitting the invasion of ER– cells. Conversely, when ER– cells are less efficient on glucose than ER+ cells, then ER– cells limited by glucose may be susceptible to invasion by ER+ cells, provided that sufficient levels of estrogen are available. ER+ cells will outcompete ER– cells when estrogen is abundant, resulting in low concentrations of interstitial glucose within the tumor. In the absence of estrogen, ER– cells will outcompete ER+ cells, leaving a higher concentration of interstitial glucose. At intermediate delivery rates of estrogen and glucose, ER+ and ER– cells are predicted to coexist. In modeling the dynamics of cells in the same tumor with different resource requirements, we can apply concepts and terms familiar to many ecologists. These include: resource supply points, R∗, ZNGI (zero net growth isoclines), resource depletion, and resource uptake rates. Based on the circumstances favoring ER+ vs. ER– breast cancer, we use the model to explore the consequences of therapeutic regimens that may include hormonal therapies, possible roles of diet in changing cancer cell composition, and potential for evolutionarily informed therapies. More generally, the model invites the viewpoint that cancer’s eco-evolutionary dynamics are a consumer-resource interaction, and that other growth factors such as EGFR or androgens may be best viewed as essential resources within these dynamics.

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“…Estrogen plays vital roles in cell survival and division of normal and carcinogenesis of BC [33]. Cells are able to recognize and utilize of estrogen through ERs [34]. Estrogen receptors are over-expressed in about 70-75% of all BC [21].…”

A resource-based mechanistic framework for castration-resistant prostate cancer (CRPC)

“…That said, our data indicate that a theoretical framework that integrates available information on the biology of resource use in a tumour with its growth dynamics could considerably expand our current toolkit for cancer control. This view has seen increasing advocacy recently (Kareva et al, 2015, Kareva and Brown, 2021) and has particular relevance for endocrine cancers, most of which frequently have a hormone or growth factor signaling axis that is crucial for cancer progression, as exemplified by the importance of EGFR signaling in breast cancer (Osborne et al, 1985, Kareva and Brown, 2021), testosterone signaling in prostate cancer (Mohler et al, 2004), or insulin signaling in pancreatic cancer (Chan et al, 2014, Archetti et al, 2015). More such signaling axes will undoubtedly be identified in the years to come and in each case, tumour composition and size could be seen as a result of the interplay between such signaling and other energetic resources, which offers much scope for further modelling effort.…”

Общие Принципы Взаимоотношений Живых Организмов С Экосистемой И Злокачественных Клеток С Живым Организмом

“…2). Такие соображения касаются глюкозы и других метаболитов, включая жирные кислоты, кетоновые тела и аминокислоты [69], а также гормонов [41].…”