The role of stromal cells in epithelial-mesenchymal plasticity and its therapeutic potential

Abstract

The epithelial-mesenchymal transition (EMT) is a critical tumor invasion and metastasis process. EMT enables tumor cells to migrate, detach from their original location, enter the circulation, circulate within it, and eventually exit from blood arteries to colonize in foreign sites, leading to the development of overt metastases, ultimately resulting in death. EMT is intimately tied to stromal cells around the tumor and is controlled by a range of cytokines secreted by stromal cells. This review summarizes recent research on stromal cell-mediated EMT in tumor invasion and metastasis. We also discuss the effects of various stromal cells on EMT induction and focus on the molecular mechanisms by which several significant stromal cells convert from foes to friends of cancer cells to fuel EMT processes via their secretions in the tumor microenvironment (TME). As a result, a better knowledge of the role of stromal cells in cancer cells' EMT may pave the path to cancer eradication.

Keywords: EMT; Secretions; Stromal cells; Tumor metastasis; Tumor microenvironments.

Fig. 1

Overview of epithelial–mesenchymal plasticity in ontogeny and tumor progression. EMT is a highly dynamic and complex yet orchestrated programme in epithelial cells that lose some features such as down-regulation of the expression of P53, RB and E-cadherin, and gain some characteristics (for example, increased motility and stemness, along with enhanced expression of Vimentin, N-cadherin, FSP1 and Fascin1) to convert to mesenchymal phenotype. Vice versa, in the reverse process MET, cells increase their epithelia attributes and decrease mesenchymal ones. EMT-TFs tightly control these two processes to maintain development during ontogeny, whereas these normal programmes are also hijacked by cancer cells to evolve [24, 28]. Remarkably, cells with partial or hybrid EMT status possess both epithelial and mesenchymal attributions

Fig. 2

The paradigm of EMT promotes tumor cells migration, invasion and metastasis. Multiple rounds of EMT process confers cancer cells with elevated expression of Fascin 1 to form filopodia, which mediates the cancer cells departing from primary lesion to entry into circulation both in the ‘Linear progression model’ and in the ‘Parallel progression model’ [70]. Then, CTCs were coated by platelets to diminish blood flow shear force avoid killing by immune cells. The cells conveyed by circulation subsequently extravasate to the parenchyma of foreign organs, followed by a MET to undergo metastatic outgrowth (the overt metastatic clone)

Fig. 3

The master pathways implicated in EMT activation. Several signaling pathways regulate EMT-TF induction, which is most evident in the cancer setting. In this scenario, cEMT or pEMT is primarily responsible for this process. By activating of the Jagged/Delta-Notch-NICD axis and the Wnt-Frizzled-β-catenin-LIF1 pathway, the ligands Jagged/Delta and Wnt induce EMT processes. Regarding the signaling pathways involved in the convergence of events that facilitate the EMT process, it has been observed that HIF-1α can recruit the glucocorticoid receptor (GR). The GR is a hormone receptor activated by glucocorticoids (GC) and certain androgen deprivation agents like enzalutamide (Enz). However, the activity of GR is inhibited by the AR. This recruitment of GR by HIF-1α enhances the expression levels of EMT-TFs in cells once they detect a hypoxic environment. The involvement of cytokine receptors, Sonic-Hedgehog, and GPCR/ GPER signaling pathways in the process of EMT has also been suggested (The image was adapted from Ref. [38])

Fig. 4

The dual roles of immune cells within TME. The schematic illustration represents communication networks between immune and cancer cells that serve as foes or accomplices in early- and late-stage. Briefly, immune cells in TME secrete a range of factors (for example, IFNβ, IFNγ, and TNF) and unleash gasotransmitters such as H2S and NO or employ pathways to kill cancer cell in the early stage of the disease. Unfortunately, these foes of cancer cells, following rounds of EMT, stepwise became friends with cancer cell to conspire in fuelling tumor progression by secretions or pathways. For instance, TGFβ, a factor of the suppressive microenvironment generated both by neutrophils and cancer cells, exacerbates the suppressive microenvironment that promotes cancer cell immune evasion, survival, and expansion. In addition, NK cells in TME can plunge the production of the IFNγ, which was utilized to inhibit cancer in the early-stage, to block the inhibitory effect in the late-stage. Meanwhile, NK cells also inreased the secretion of Wnt to fuel cancer cell growth in contrast to the direct cytotoxic effect of CD8⁺ T-cell in the early-stage, which was highjacked by cancer cells to facilitate cancer cell escape from adverse milieu through stat3/FAO and DNA repair pathways to survival

Fig. 5

Summary of major stromal cells supporting tumor cell EMT via their secretions. Tumor microenvironments contain three main types of stromal cells that secrete diverse signal molecules. These secreted molecules, such as we enumerated, initiate tumor cell EMT programmes in a paracrine manner via binding to their receptors. For example, both E2 and chemokines can directly bind to GRCR/GPER of cancer cells to fuel EMT. Additionally, E2 can also stimulate tumor cell EMT through ERα activation. Cytokines, growth factors, and components of ECM facilitate tumor cell EMT by cytokine receptors signalling, TGF-β, RTK, and Integrin pathways, respectively. Notably, the marked secretions (red) listed here have either been shown elsewhere to promote tumor cell EMT, or at least there is currently no direct evidence to support tumor cell EMT activation