Sleeping Beauty and the Microenvironment Enchantment: Microenvironmental Regulation of the Proliferation-Quiescence Decision in Normal Tissues and in Cancer Development

Abstract

Cells from prokaryota to the more complex metazoans cease proliferating at some point in their lives and enter a reversible, proliferative-dormant state termed quiescence. The appearance of quiescence in the course of evolution was essential to the acquisition of multicellular specialization and compartmentalization and is also a central aspect of tissue function and homeostasis. But what makes a cell cease proliferating even in the presence of nutrients, growth factors, and mitogens? And what makes some cells “wake up” when they should not, as is the case in cancer? Here, we summarize and discuss evidence showing how microenvironmental cues such as those originating from metabolism, extracellular matrix (ECM) composition and arrangement, neighboring cells and tissue architecture control the cellular proliferation-quiescence decision, and how this complex regulation is corrupted in cancer.

Quiescence, an individual journey

“…On the one hand, quiescence induced by macro-or micro-environmental conditions can theoretically be separated from quiescence that is coupled to differentiation as part of a programmed developmental plan (O'Farrell 2011; Fiore et al 2018). On the other hand, various quiescence "degree" can be ascribed depending on cell's "activities".…”

“…Moreover, quiescence establishment and exit, through the regulation of cell proliferation, have to be tightly controlled to avoid pathological situations including stem cell depletion and tumorigenesis (Orford and Scadden 2008; O'Farrell 2011; Cheung and Rando 2013;Dhawan and Laxman 2015). Interestingly, more and more evidences argue that microenvironment -both its composition and physical properties -plays a central role in regulating quiescence(Linde et al 2016;Fiore et al 2018). This is particularly true in the case of disseminated tumor cells that persist far from the primary tumor as undetectable quiescent individual cancer cells, the awakening of these malignant cells being thought to be the major cause of cancer recurrence(Aguirre-Ghiso et al 2013;Sosa et al 2014;Linde et al 2016;Fiore et al 2018).…”

Impact of Hydrogel Elasticity and Adherence on Osteosarcoma Cells and Osteoblasts

“…Unlike normal cells, which are anchorage dependent, cancer cells always arrest upon contact with extracellular matrix (ECM). The difference between cancer cells and their normal counterpart elicits different cellular responses to the matrix . For example, a prominent invasively transition of cancer cells occurs independent of mechanics of ECM, while cell migration, proliferation, and differentiation of normal cells rely on ECM adhesivity .…”

Phenotypic melanoma heterogeneity is regulated through cell-matrix interaction-dependent changes in tumor microarchitecture

“…Elevated activity of the Rho-ROCK-myosin signaling axis is typically associated with increased proliferation via promotion of cell contractility, cell adhesion, cytokinesis, oncogene activation and regulation of cell cycle proteins. Nevertheless, there is a number of studies reporting an opposite role of the Rho-ROCK-myosin signaling pathway through negative feedback on growth factor signaling (Nakashima et al, 2010) and promotion of tumor suppressor genes such as PTEN (Fusella et al, 2014;Yang and Kim, 2012), p21 (Olson et al, 1998;Taubenberger et al, 2019) and p27 kip (Hu et al, 1999;Vidal et al, 2002). It has been speculated that ROCK contractility may simply act as a necessary mediator of cell structural changes which in turn would impact cell cycle protein levels, for instance p27 kip regulation by PKCα-PKB-FoxO signaling that is initiated by stretch-stress-activated calcium channels (Delarue et al, 2014).…”

“…In addition to genetic and epigenetic factors, the microenvironment plays a pivotal role in determining the cycling state of a cell. Beyond well-known determinants of proliferation and quiescence such as nutrients, growth factors and mitogens, another factor has been largely implicated in regulating cell proliferation, both in normal tissue and in cancer: the extracellular matrix (ECM) (Fiore et al, 2018;Pickup et al, 2014). With its multitude of biochemical and biomechanical properties, the ECM not only acts as a scaffold to determine tissue morphology and physical characteristics, but also influences signaling and biology of the cells it surrounds (Jansen et al, 2017;Ju et al, 2018).…”