Mini-reviewMicroenvironment and tumor cell plasticity: An easy way out
Highlights
► The plasticity in cell motility is an essential feature for the metastatic process. ► Tumor microenvironment promotes cell plasticity. ► Role of hypoxia, acidity, ECM stiffness and stromal cells in tumor cell plasticity.
Introduction
It is now well established that genetic changes of the tumor cell itself are insufficient to account for tumor progression and metastasis and that several epigenetic alteration can profoundly affect several features of cancer cells during their progression towards malignancy. Both tumor environmental cues and cell-intrinsic alterations contribute to these epigenetic changes, inducing adaptations by cancer cells that allow successful invasion of the stroma, entry and survival into lymphatic or blood vessels, spread and colonization of distant/different organs, as well as resistance to cytotoxic drugs [1].
Among challenging conditions acting on cancer cells during their progression towards malignancy and affecting their plasticity through adaptive strategies, we can include microenvironmental factors, as interaction with stromal cells, macrophages or exposure to hypoxia, metabolic reprogramming due to epigenetic control, as well as endoplasmic reticulum stress and resistance to antineoplastic drugs (Fig. 1). Common adaptive responses include enhanced plasticity in cell motility, resistance to apoptosis/anoikis and survival in an hostile environment characterized by hypoxia, acidity, inflammatory cytokines delivery, as well as induction of the so-called unfolded protein response, leading cancer cell to enhance resistance to apoptosis and to cytotoxic drugs.
Stress-adaptive strategies engaged by cancer cells very frequently share a state of oxidative stress (OS), that adjusts cancer cell phenotype through epigenetic responses driven by redox-sensitive transcription factors [2], [3]. Indeed, oxidative stress can activate a variety of transcription factors including nuclear factor-κB (NF-κB), AP-1, p53, hypoxia-inducible factor-1 α (HIF-1α), PPAR-γ, β-catenin/Wnt, and NF-E2-related factor (Nrf2). On the other side, sustained OS sensitizes cells to activate antioxidant response, driven again by redox-sensitive transcription factors, which strongly concurs to combat OS and to enhance adaptive responses of tumor cells to unfavorable environmental conditions as hypoxia, nutrient deprivation and drug therapy [4], [5].
One of the main features of invasive growth is the ability of metastatic cancers to shift motility modes to elude anticancer treatments, which represents a major challenge for developing strategies aimed at blocking the spread of cancer cells. Several elements of the tumor milieu are able to elicit a clear escape adaptive strategy, called epithelial mesenchymal transition (EMT), an epigenetic program that leads epithelial cells to lose their cell–cell and cell-ECM interactions to undergo cytoskeleton reorganization and to gain morphological and functional characteristics of mesenchymal cells, upon EMT cells can move away from the stressful and hostile site of the primary tumor [6], [7], [8]. EMT is a regulated process in which the cell loses its epithelial markers and achieves expression of mesenchymal markers [9]. Several transcription factors have been implicated in the control of EMT, including Snai1, Slug, Twist, Goosecoid, ZEB1, and SIP1 [8], [10]. A properties of EMT is the loss of E-cadherin expression, correlated with the tumor grade and stage [11]. Beside EMT, the ability of metastatic cancer to shift from mesenchymal to amoeboid motility (MAT) has also been reported. This is a squeezing adaptive movement of cells which are able to cross matrix barriers, avoiding the use of metalloproteases (MMPs) and integrin leakage, thus resisting to common anticancer drugs targeting proteases or integrins [6], [12], [13].
Tumor microenvironment, including extra-cellular matrix (ECM) components, accessory fibroblasts, and pro-inflammatory cells, has recently received particular attention. Indeed, tumor-stroma interaction at both the primary and secondary tumor sites, may allow and support tumor survival and outgrowth, organ homing and invasion. The role of tumor support played by stromal cells spans from growing of new vessels, with the recruitment of endothelial progenitors and their activation to form functional vessels, to secretion of a large amount of cytokines and soluble factors affecting cancer cell behavior. Several components of the microenvironment, including cancer associated fibroblasts (CAFs), macrophages and hypoxia, are intimately or causally linked with oxidative stress, which is a molecular motor for several adaptive strategies. Cancer cells take advantage of this OS, exploiting it to engage EMT, to achieve stem traits favoring metastatic spread, as well as to develop tumor chemo- and radio-resistance [2], [14], [15].
Hypoxia is a concomitant microenvironmental factor, considered as an independent negative prognostic indicator and to contribute to cancer progression affecting the behavior of both cancer and stromal cells [16]. The effects of intratumoral hypoxia in cancer cells can be essentially distributed to four classes: (i) activation of a glycolytic metabolism to circumvent lack of oxygen, (ii) activation of a motogen program, mainly through EMT, in order to escape from the hostile environment, (iii) activation of pathways for survival to stressful conditions, (iv) secretion of soluble growth factors eliciting de novo angiogenesis allowing nutrient/oxygen supply. By the way, hypoxia strongly influences also stromal cells, essentially affecting the profibrogenic/proangiogenic behavior of CAFs.
Metabolic adaptations through reprogramming towards a Warburg metabolism has been included in the revised perspective of the Hallmarks of Cancer by Hanahan and Weinberg [17]. Indeed, rising evidence have now established that cancer cells undergo a specific metabolic reprogramming towards opportunistic behavior, leading cancer cells to gain several advantages, largely beyond the simple ATP production. Cancer cells primarily use glucose by aerobic glycolysis, producing lactate (the so-called Warburg effect). The Warburg effect, coupled with increased glucose uptake due to incomplete glucose oxidation, facilitates in cancer/proliferating cells the efficient anabolism of macromolecules [18].
Finally, drug resistance is a multifactorial adaptive phenomenon involving multiple pathways and, among them, changes in cellular responses, such as increased cell ability to tolerate stress conditions and acquire mechanisms to escape apoptosis. In such a perspective, adaptive responses of tumor cells to unfavorable environmental conditions (i.e., hypoxia, nutrient deprivation, reactive oxygen species-ROS) represent major mechanisms responsible for resistance to apoptosis and drug therapy. Inappropriate activation of signaling pathways could occur during acute or chronic stress as a result of protein misfolding, protein aggregation, or disruption of regulatory complexes. Levels of heat shock proteins are elevated in many cancers, and correlate with poor prognosis in terms of survival and response to therapy [4].
Adaptation to survive to cytotoxic drugs, protection of DNA integrity and metabolic reprogramming are intimately linked, and again redox circuitries are involved [19], [20]. Indeed, levels of Nrf2, the master transcription factor driving antioxidant response, are correlated with resistance to chemotherapeutic drugs such as cisplatin, doxorubicin, and etoposide. Moreover, many kelch-like ECH-associated protein 1 (Keap1) mutations or loss of heterozygosity in the Keap1 locus have been identified in lung cancer cell lines or cancer tissues. Keap1 mutations or loss of heterozygosity resulted in inactivation/elimination of Keap1, which upregulated the protein level of Nrf2 and transactivation of its downstream genes. These protective effects exerted by Nrf2 often lead to enhanced defenses from oxidative stress-related diseases, providing a selective advantage for cancer cells to survive OS under treatment with cytotoxic drugs [21].
Among these complex and interrelated features of tumor cell plasticity, our review will mainly focus on the role of tumor microenvironment on plasticity of cell motility, addressing the role of structural and stromal components.
Section snippets
Plasticity of cell motility by ECM stiffness
Matrix invasion, one of the earliest steps in the metastatic process and a key determinant of the metastatic potential of tumor cells, is not only based on intrinsic genetic and biochemical properties of cancer cells. Indeed, the invasion process can only be understood in the context of the cancer cell interactions with its microenvironment [22]. The ECM provides a structural and molecular frame for the moving cell body and thereby impacts the strategy and efficiency of cell migration.
The ECM
Plasticity of cell motility by hypoxia
Cancer cell proliferation, as well as the progression towards an aggressive and malignant phenotype, requires sufficient supplies of nutrients including carbon sources, nitrogen sources, and molecular oxygen to optimize cell catabolism through respiration. Carbon sources and molecular oxygen are critical for three key points: (i) the generation of energy in terms of ATP, (ii) the maintenance of sufficient building blocks for anabolic purposes, (iii) the maintenance of intracellular redox status
Plasticity of cell motility by acidity
Invasive tumor cells acquire various adaptive characteristics during their long route towards malignancy [17]. Deregulated pH is emerging as another adaptive response of most cancers. Indeed, cancer cells, regardless of their origin and genetic background, show a ‘reversed’ pH gradient with a constitutively increased intracellular pH (pHi) that is higher than the extracellular pH (pHe) [100]. In normal adult cells, pHi is generally ∼7.2, while pHe is ∼7.4. On the contrary, cancer cells have a
Plasticity of cell motility by CAFs
CAFs represent the activated form of fibroblast found in association with cancer cells, that have acquired contractile and secretory characteristics [76], [149]. Indeed, they share with myofibroblasts, the activated form of fibroblasts detected during wound healing and fibrosis, the expression of α-smooth muscle actin which confers high contractile properties, but unlike what happens for myofibroblasts, CAF activation is not reversed once the activating stimulus is attenuated, so their presence
Plasticity of cell motility by endothelial progenitor cells (EPCs)
EPCs are derived from the bone marrow (BM) and peripheral blood (PB), contributing to tissue repair in various pathological conditions through neovascularization, that is the creation of new blood vessels [220]. EPCs are recruited into the circulation in response to growth factors and cytokines released following stimuli such as vascular trauma, wounding and cancer. Indeed, tumors secrete growth factors such as VEGF that promote mobilization of EPCs to sites of vasculogenesis [221]. EPCs are
Plasticity of cell motility by cancer associated macrophages (CAMs)
CAMs constitute a significant part of the tumor-infiltrating immune cells and are key actors in the link between inflammation and cancer [257], [258]. Macrophages are released from the bone marrow as immature monocytes, after circulating in the bloodstream are recruited by diverse chemokines such as CCL2, CCL5, CCL7, CXCL8 and CXCL12 secreted by neoplastic and stromal cells, migrate to different areas of tumor microenvironment and differentiate according to surrounding cellular or environmental
Conclusion
Proofs about the conditioning by tumor microenvironment on cancer cells are rapidly accumulating within the recent literature. Worryingly, this conditioning is able to affect in a pleiotropic manner several features correlating with malignancy, eliciting adaptations to key steps of the metastatic process. Honestly, there are too many adaptive mechanisms to believe that a therapeutic strategy based on only a few of them will succeed. To date, the most promising pharmacological approach is the
Acknowledgements
This study was supported by the Associazione Italiana Ricerca sul Cancro (AIRC), Istituto Toscano Tumori and Regione Toscana (TUMAR).
References (278)
- et al.
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
Cell Signal.
(2012) Prespecification and plasticity: shifting mechanisms of cell migration
Curr. Opin. Cell Biol.
(2004)- et al.
The epithelial–mesenchymal transition under control: global programs to regulate epithelial plasticity
Semin. Cancer Biol.
(2012) - et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Metabolic reprogramming: a cancer hallmark even warburg did not anticipate
Cancer Cell
(2012) - et al.
Oxidative stress, inflammation, and cancer: how are they linked?
Free Radic. Biol. Med.
(2010) - et al.
Tensional homeostasis and the malignant phenotype
Cancer Cell
(2005) - et al.
Curr. Biol.
(2006) - et al.
Microarchitecture of three-dimensional scaffolds influences cell migration behavior via junction interactions
Biophys. J.
(2008) - et al.
Extracellular matrix determinants of proteolytic and non-proteolytic cell migration
Trends Cell Biol.
(2011)