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Ye, M.; Huang, X.; Wu, Q.; Liu, F. Promotion of Senescent Stroma for Tumor Progression. Encyclopedia. Available online: (accessed on 18 June 2024).
Ye M, Huang X, Wu Q, Liu F. Promotion of Senescent Stroma for Tumor Progression. Encyclopedia. Available at: Accessed June 18, 2024.
Ye, Minghan, Xinyi Huang, Qianju Wu, Fei Liu. "Promotion of Senescent Stroma for Tumor Progression" Encyclopedia, (accessed June 18, 2024).
Ye, M., Huang, X., Wu, Q., & Liu, F. (2023, April 16). Promotion of Senescent Stroma for Tumor Progression. In Encyclopedia.
Ye, Minghan, et al. "Promotion of Senescent Stroma for Tumor Progression." Encyclopedia. Web. 16 April, 2023.
Promotion of Senescent Stroma for Tumor Progression

Cellular senescence is a unique cellular state. Senescent cells enter a non-proliferative phase, and the cell cycle is arrested. However, senescence is essentially an active cellular phenotype, with senescent cells affecting themselves and neighboring cells via autocrine and paracrine patterns. A growing body of research suggests that the dysregulation of senescent stromal cells in the microenvironment is tightly associated with the development of a variety of complex cancers. 

cellular senescence stromal cell tumor microenvironment

1. Introduction

Decades ago, Krtolica et al. demonstrated the capacity of senescent fibroblasts to promote tumorigenesis, indicating cellular senescence as a case of evolutionary antagonistic pleiotropy that, despite restraining tumor growth in the early stages, may nevertheless exhibit pro-tumorigenic effects when senescence occurs in benign stromal cells [1]. Emerging evidence supports the role of senescent stromal cells as an accomplice in the growth of a variety of epithelial-derived solid tumors [2][3][4]. Similarly, recent studies have shown that senescent mesenchymal stromal cells contribute to the development of myeloid tumors [5][6][7][8]. The positive effect of the senescent stroma on tumor progression has been well established, but behind the scenes are the molecular mechanisms that link senescent stroma, cancer cells, and the TME.
Senescent stromal cells release SASP factors into the TME, thereby affecting malignant cells and ECM. SASP is the linchpin in understanding the tumor promotion by senescent stromal cells. SASP factors induce and enhance tumor cell senescence in both paracrine and autocrine ways to arrest tumor cell proliferation [9][10]. Ironically, numerous SASP factors promote tumor growth and migration in very different contexts [2][11][12][13], ultimately paving the road to hell.

2. Epithelial–Mesenchymal Transition (EMT)

EMT refers to the cellular process of reversible transformation of epithelial cells into mesothelial cells and plays a momentous role in oncogenesis [14]. When epithelial-derived malignant cells receive signals from the TME, the expression of many genes is activated or inhibited by epigenetic modifications, leading to a phenotypic conversion [15]. During EMT, the expression of epithelial cadherin (E-cadherin), a component responsible for adhesion junctions in epithelial tissues arranged regularly with originally apical-basal polarity, is suppressed, and the typical polygonal, cobblestone morphology of epithelial cells is gradually lost, progressively changing to a spindle-shaped mesenchymal morphology [15][16]. Ultimately, cancer cells that undergo EMT acquire a potentially more malignant phenotype and exhibit an enhanced ability in proliferation, invasiveness, and resistance.
EMT is a non-cell autonomous process, meaning that the initiation of the EMT program requires modulation from external contributors. Hypoxia and external agents in the TME are critical signals, while molecules secreted by various active stromal cells, including senescent stromal cells, are also known sources that elicit EMT [16]. Senescent stromal cells release SASP factors to induce EMT of cancer cells via paracrine secretion. The signaling pathways that have been shown to robustly initiate the EMT program are TGF-β, WNTs, NOTCH, and mitogenic growth factors [15], and multiple studies support the involvement of SASP factors produced by senescent stromal cells.
A study evaluating the role of senescent peritoneal mesothelial cells (HPMCs) in colorectal cancers found that conditioned medium (CM) of senescent HPMCs promoted the colorectal cancer cell line SW480 to undergo EMT, closely associated with stromal-derived TGF-β1 [17]. In the context of hepatocellular carcinoma, upregulation of TGF-β and EMT promotion in cancer cells were also observed following hepatic stellate cell senescence [18]. Other SASP factors that facilitate EMT in cancer cells include the pro-inflammatory factors IL-6 and IL-8 [18][19], Serine protease inhibitor Kazal-type 1 (SPINK1) [12], amphiregulin (AREG) [13][20], epiregulin (ERPG) [21], and WNT16B [20]. These SASP factors are secreted in the context of DNA damage and are directly or indirectly implicated in the regulation of the cancer cell EMT program.
Following the interaction of SASP factors with cell surface receptors, specific intracellular molecules are activated to initiate the EMT procedure. The SMAD signaling pathway plays a vital role in EMT development. TGF-β binds to a complex of TGF-β receptor type 1 (TGFβR1) and TGFβR2 on the cell surface, which in turn activates SMAD2 and SMAD3, the latter two forming a trimer with SMAD4, which enters the nucleus as a transcription factor to regulate the expression of EMT-transcription factors [15][22]. In addition, several studies have shown that SASP factors activate non-SMAD pathways to promote EMT; for example, IL-8 initiates the JAK2-STAT3-SNAIL pathway in the context of hepatocellular carcinoma, and AREG activates EGFR, which in turn initiates the PI3K/Akt/mTOR and MAPK pathways to induce EMT in the context of prostate cancer [13][18]. Yet more studies have only confirmed the induction of EMT by SASP factors, and the detailed mechanisms have not been explored in depth.
The expression of mesenchymal cell biomarkers is progressively increased following EMT induction. The altered cell phenotype is accompanied by reduced E-cadherin expression and disruption of cell junctions, facilitating cancer cell migration [15]. Intriguingly, EMT is also frequently observed to increase cancer cell stemness, promote angiogenesis, and remodel ECM, protumor effects that are induced by senescent stromal cells and will be discussed subsequently. This demonstrates the complexity and magnitude of the function of stroma-derived SASP factors in neoplasia regulation.

3. Cancer Stem Cells (CSCs) and Cancer Stemness

Cancer cell populations are heterogeneous, with different phenotypes of cancer cells differing significantly in terms of proliferation, invasiveness, and tolerance. In this respect, CSCs refer to a subset of the cancer cell population with major properties including self-renewal, clonal tumor initiation capacity, and clonal long-term reproductive potential [23]. Two main viewpoints existed in the past regarding the provenance of CSCs. The hierarchical model suggests that CSCs are derived from stem cells that evade surveillance and undergo a malignant transformation, and that this particular population generates short-lived offspring through continuous self-renewal, similar to the biological behavior of stem cells [24][25]. The other model, the stochastic model, suggests that every cancer cell shares the opportunity equally to convert into CSCs and participate in promoting tumorigenesis [23][26]. Whereas the proposal of CSC plasticity reconciles the two theories, differentiated cancer cells receive specific signals from the adjacent microenvironment and experience dedifferentiation back into the CSC pool, which may be driven both by an innate genetic profile (the hierarchical theory) and by stem cell-like permissive epigenetic modifications (the stochastic theory) [23][27].
Having understood the generation of CSCs, another question is the driving force behind the incremental increase of CSCs in the cancer cell population, or what factors lead to the conversion of non-CSCs to CSCs. The TME, as the extrinsic environment of cancer cells, is an asset in the modulation of cancer cell plasticity [27][28]. Colorectal cancer models underpin research to understand the mechanisms. The process of colorectal cancer establishment is complemented by the activation of NF-κb and the constant stimulation of inflammation, which is reminiscent of biological features of senescent stromal cells and SASP factors [27]. Indeed, there is growing evidence that senescent stromal cells release SASP factors, which cause non-CSCs to dedifferentiate and transmute into more malignant CSCs.
As staple members of the SASP factors, the proinflammatory IL-6 and IL-8 are recognized for their role in the generation of CSCs. Breast cancer models provide support for understanding the interaction between senescence-related inflammation and cancer stemness. Kim et al., in an elegant experiment, furnished direct testimony that IL-6 regulates stemness-associated gene OCT-4 activity in differentiated cancer cells via the JAK1/STAT3 pathway [29]. A study confirmed the vital impact of environmental selection represented by the TME on cancer stemness promotion. A trastuzumab-tolerant breast cancer model was constructed by knocking out the PTEN gene in HER2 overexpressing breast cancer cell lines to simulate the environment of long-term trastuzumab administration, demonstrating upregulation of proinflammatory factor expression in the context of PTEN deletion and eventual expansion of the CSCs population through the IL-6 inflammatory loop [30]. Further studies have shown that treatment with IL-6- or IL-8-enriched senescence CM induces a self- and cross-reinforced senescence/inflammatory milieu, rendering the otherwise less aggressive MCF-7 breast cancer cells stemness-enhanced [19], which was consistent with another study concerning the effect of IL-8 on MCF-7 breast cancer cells [31]. In lieu of breast cancer, one study, in the context of colon cancer, demonstrated that IL-8 targeting of CXCR2 facilitated the orientation of human-bone-marrow-derived mesenchymal stem cells towards the CSC population, thereby fostering the creation of a niche in favor of CSCs [32]. Unfortunately, the above reports focus on the effects of IL-6 and IL-8 on cancer cells in terms of stemness promotion and malignant phenotypic alterations, while it remains unproven whether IL-6 and IL-8 production is associated with senescent stromal cells. A report revealed that myofibroblast-derived IL-6 and IL-8 activate the NOTCH/HES1 and STAT3 pathways to enhance cancer stemness in colon cancer [33]. Considering the nature of the overlap between CAFs, senescent fibroblasts, and myofibroblasts (see BOX1), this could be perceived as a compelling argument for the expansion of the CSCs population by senescent stromal cells via proinflammatory SASP factors. The impact of miscellaneous SASP factors on the improvement of stemness remains to be investigated. A study illustrated that SPINK1 reprograms cancer cell transcriptome-wide expression to promote EMT and CSC growth [12]. However, whether senescent stromal cells enhance cancer stemness by producing pro-inflammatory SASP remains controversial, and this void requires support from additional experimental evidence.
Another reason to propose that SASP promotes stemness is that blocking NF-κb, the major SASP regulator, remarkably reduces stemness [34][35]. This raised new thinking about whether blocking NF-κb to inhibit the expansion of CSCs is relevant to preventing senescence amplification mediated by paracrine signals in the TME [35]. As previously discussed, cancer cells are also susceptible to senescence, and cellular senescence is an integral cellular program that limits tumor progression. Moreover, numerous pieces of evidence give the stereotype that the tumor-promoting effects of cellular senescence are associated with bystander effects, which interfere with the physiological function of stromal cells, whereas the senescence of tumor cells themselves is anti-neoplastic. Intuitively, the features of senescent cells and stem cells are not compatible. However, the discovery by Milanovic et al. provides an insight into the fact that senescent cancer cells are still allowed to return to the cell cycle and dedifferentiate into CSCs to devastate more severely [36]. A possible explanation is that under selective pressure, cancer cells undergo senescence and selectively fit clones, i.e., cancer stem cell populations grow and spread, acquiring more aggressive tumorigenicity and metastasis. Considering the contribution of exogenous drugs and toxicants to both bystander cell senescence and tumor stemness elevation [34][37], it is tempting to rethink the link between senescence and stemness and the role that SASP-mediated paracrine senescence plays in both. It is currently recognized that the presence of senescence-associated stemness is a mechanism inherent in the evolutionary process to cope with stressful damage and ironically confers on tumor cells superior survivability in hostile conditions [36]. Yet these results were accomplished with artificial intervention; to better validate the experimental results, spontaneous models are required to further gauge the effects of spatiotemporal factors and guide a better understanding of the relationship between cellular senescence and cancer cell stemness.

4. Angiogenesis

Angiogenesis refers to the establishment of new blood vessels from pre-existing vessels [38]. Angiogenesis is vital to tumor growth, with new capillaries improving the degree of hypoxia and transporting nutrients and metabolites for the tumor. A variety of pro- and anti-angiogenic forces are present in the TME; they interact to determine angiogenesis activity within the tumor [39]. Tumor vascularization is initiated when pro-angiogenic forces are predominant, a process called “the angiogenic switch” [40]. Of all the pro-angiogenic forces, without a doubt, angiogenic factors are predominant. The three most recognized angiogenic factors are the vascular endothelial growth factor (VEGF), the fibroblast growth factor (FGF), and the platelet-derived growth factor (PDGF) [38]. A multitude of cytokines secreted by senescent stromal cells, meanwhile, crosstalk with angiogenic factors and thus impinge on the angiogenic switch.
Cultivating three different types of breast cancer cell lines by CM derived from young and senescent HPMCs, it was observed that the secretory levels of pro-angiogenic agents, including CXCL1, CXCL8, the hepatocyte growth factor (HGF), and the VEGF, were significantly increased in cancer cells [41]. Senescent HPMCs were proven to modulate cancer cells by secreting IL-6 and TGF-β1, promoting tumor vascularization through HIF-1α, NF-κb/p50, and AP-1/c-Jun pathways [41]. A subsequent article demonstrated that senescent populations in ovarian cancer cells induce normal HPMC senescence via paracrine secretion to cause stromal cell secretome reprogramming, ultimately resulting in a vicious cycle, offering an understanding of the spontaneous process of de novo tumor development [42]. These senescent immune cells in the TME not only upregulate the secretion of the pro-angiogenic agents matrix metalloproteinase (MMP)9, VEGF-A, and IL-8 but also reduce the synthesis of IP-10 (also known as CXCL10), an important angiogenesis inhibitor, thereby triggering the “angiogenic switch” [43]. Altogether, these studies gave support to the role of senescent stromal cells in the facilitation of angiogenesis.

5. ECM Remodeling and MMPs

As a non-cellular component of the TME, the ECM deposited by fibroblasts, is critical to the maintenance of tissue integrity, while ECM remodeling, which involves basement membrane disintegration, is universal in the maintenance of physiological homeostasis and abnormal pathological alterations [44]. In the tumor context, ECM remodeling is tightly linked to tumor proliferation, angiogenesis, and distant metastasis.
Stromal-derived SASP factors are involved in ECM remodeling. Among them, the most essential group is MMPs. The upregulation of MMPs in senescent fibroblasts was extensively reported. One of the main models applied to study and understand age-related chronic inflammation is the aged-skin model [45]. In aged skin, MMPs cause disruption of tissue homeostasis by degrading the ECM. It has previously been shown that senescent fibroblasts promote early tumor growth by secreting MMP1 (interstitial collagenase) and MMP2 (72kDa type IV collagenase), which modulate PAR1 in malignant cells via a paracrine manner [46]. Further investigations proved that MMPs and PAR1 are upregulated in aged skin compared to young, healthy samples [46]. More studies revealed that tumor invasion facilitated by MMPs is not limited to skin cancer. Bleomycin-induced senescent fibroblasts stimulate early growth of MDA-MB-231 cells (breast cancer model), and administration of the MMP inhibitor GM6001 reversed this effect [47], which was consistent with ionizing-radiation-induced senescent human lung fibroblasts in the context of lung cancer [48]. In addition, MMPs also affect cancer prognosis. In contrast to the better prognosis subtype, the genetically stable OSCC, CAFs derived from genetically unstable OSCC exhibited upregulation of MMP2 and a corresponding greater contribution for ECM destruction and keratinocyte discohesion [49]. Senescent HPMCs promote peritoneal metastasis in colorectal cancer, and the enhancement of tumor aggressiveness is due to increased expression levels of several SASP factors, including MMP-3 [17]. Altogether, SASP factors, especially MMPs contribute to tumorigenesis and poor prognosis via ECM remodeling, which is another convincing piece of evidence for the detrimental effects of senescent stromal cells.


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