The differentiation of normal fibroblasts into CAFs is one of the cornerstones of early tumor initiation in many cancer types [83,84]. CAFs can disrupt the local ECM and deliver proliferative paracrine signals to support tumorigenic events. Interestingly, mice with fibroblast-selective PPARβ/δ deletion developed fewer and smaller skin tumors than wild-type mice exposed to topical carcinogens [85]. Similar results were recapitulated using chemically and genetically induced intestinal carcinogenesis in these mutant mice [86], indicating that PPARβ/δ activity in stromal fibroblasts promotes tumor initiation. The delayed tumor emergence in the mutant mice was due to an enhanced antioxidant response in the epithelium. Mechanistically, PPARβ/δ-knockout fibroblasts markedly increase the Nox4-derived H₂O₂ production in the adjacent epidermis, subsequently triggering an RAF/MEK-mediated NRF2 activation that elicits a strong antioxidant and cytoprotective response [85]. By reducing the phosphorylation of many tumor suppressors and oncogenes, NRF2 also increases the tumor suppressor activity of PTEN and reduces the oncogenic activity of Src and Akt, leading to delayed tumor growth [85]. Hence, reducing the expression and activity of PPARβ/δ in CAFs may provide a new therapeutic option to disrupt cancer susceptibility in the neighboring tumor epidermis.

Leucine-rich-alpha-2-glycoprotein 1 (LRG1) and TGFβ1 underpin a crucial process in the PPARβ/δ-mediated stromal–epithelial crosstalk. PPARβ/δ in fibroblasts upregulates the expression of LRG1, which blunts the epidermal response to TGFβ1 [87]. Furthermore, exogenous LRG1 can also ablate the influence of TGFβ1 on ROS generation and NRF2 activity [85]. In colorectal carcinoma and pancreatic ductal adenocarcinoma patients, the level of LRG1 in the TME and bloodstream is significantly higher than in healthy individuals and correlates positively with a more advanced cancer stage and poorer prognosis [88,89,90]. This observation suggests a pro-tumorigenic role of LRG1. Surprisingly, the LRG1 promoter has two putative PPAR response elements [91]. The expression of LRG1 is increased by a PPARβ/δ agonist, GW501516, which strongly suggests that LRG1 is a direct target of PPARβ/δ [91]. Therefore, during the early stage of tumorigenesis, CAF PPARβ/δ may stimulate LRG1 expression, which interferes with TGFβ1-dependent redox homeostasis, to support a sustained oncogenic transformation in the surrounding tumor epithelium.

Collectively, these findings uncover a major role for stromal PPARβ/δ in the epithelial–mesenchymal communication and cellular oxidative response in tumor development (Figure 3). Notably, this novel role of PPARβ/δ was primarily documented, so far, in nonmelanoma skin carcinoma and colorectal cancer models. Thus, further validation in other cancer models is necessary.

Hypoxic regions often arise because of rapid tumor growth, which outgrows the oxygen perfusion and nutrient supply from existing vasculature [92]. Cancer cells mitigate the predicament by releasing pro-angiogenic factors that stimulate angiogenesis, which is affected by all three PPAR isotypes.

In terms of PPARα, synthetic PPARα agonists such as fenofibrate and Wy-14643 have demonstrated suppressive effects on endothelial cell proliferation, neovascularization, and tumor xenograft growth [93,94]. Such anti-angiogenic effects of PPARα agonists were lost in PPARα-deficient mice transplanted with PPARα-intact tumor cells, implying that PPARα activation in surrounding stromal cells, but not the tumor cells, attenuated tumor angiogenesis [93,94]. The underlying mechanism is associated with increased anti-angiogenic factors (i.e., thrombospondin-1 and endostatin) and the interference of pro-angiogenic factor biosynthesis (i.e., VEGF-A, angiopoietin-1, and angiopoietin-2), affecting VEGF- and FGF2-mediated endothelial proliferation and migration [93,95]. Furthermore, by transcriptionally suppressing the expression of endothelial P450 CYP2C epoxygenase, whose function is to catalyze arachidonic acid epoxidation, PPARα also diminishes the epoxygenase products, epoxyeicosatrienoic acids, which are pro-angiogenic [96]. Thus, PPARα activation in stromal endothelial cells inhibited the biosynthesis of pro-angiogenic factors while promoting the secretion of anti-angiogenic factors, thereby abrogating angiogenesis and limiting nutrient supply to attenuate tumor progression.

In contrast to PPARα, PPARβ/δ is a pro-angiogenic nuclear receptor in line with its wound healing properties [97,98,99]. The activation of PPARβ/δ in endothelial cells by synthetic ligands or genetic manipulation consistently results in aberrant biosynthesis of VEGF, PDGFR, and c-KI, as well as accelerated endothelial cell proliferation and vascular formation [100,101]. In the TME, these pro-angiogenic changes stimulate the formation of a tumor with a higher vessel density, enhancing tumor feeding, oxygen provision, and metastasis capacity of the cancer cells [101]. Interestingly, in PPARβ/δ knockout mice harboring experimental wild-type tumors, the endothelial cells forming the microvessels in the tumors appear immature, hyperplastic, and less well-organized, leading to abnormal microvasculature and restricted blood flow into the tumors [102,103]. Apart from conventional growth factors, other potential PPARβ/δ-dependent angiogenic mediators include CDKN1C [102], IL-8 [104], CLIC4, and CRBP1 [105]. Considering its regulatory effects on many angiogenic genes and the strong linkages with advanced cancer stages, tumor recurrence, and distant metastasis, PPARβ/δ is identified as one of the pro-angiogenic signaling hubs in cancers [103]. Thus, the pro-tumorigenic and pro-angiogenic activities of PPARβ/δ warrant the development of efficacious PPARβ/δ antagonists to be tested in cancer models.

Existing evidence on the role of PPARγ in angiogenesis remains ambiguous. Like PPARα, PPARγ activities in the TME are associated with the dysregulated production of angiogenic factors, especially platelet-derived endothelial cell growth factor (PD-ECGF) and fibroblast growth factor (FGF) [106,107]. Early studies generally concluded on an inhibitory effect of PPARγ ligands on endothelial cell proliferation in response to pro-angiogenic factors and endothelial tube formation [108,109], whereas subsequent investigations suggested otherwise [110,111]. Such conflicting findings may be attributable to the dosages of PPARγ ligands and endothelial cell types [112]. Regardless of the pro- or anti-angiogenic properties, VEGF/VEGFR signaling is coherently implicated in the PPARγ-mediated effect [108,109,110]. A recent study using endothelial-specific PPARγ knockout models shed new light on the role of this nuclear receptor in angiogenesis. In mature endothelial cells, PPARγ knockdown impaired proliferation, migratory properties, and tubule formation capacity [111]. These impairments translated into the loss of circulating endothelial progenitor cells and angiogenic capacity in endothelial-specific PPARγ-deficient mice, which was reversed by the transplantation of wild-type bone marrow [111]. Mechanistically, abolishing PPARγ in the endothelial cells disrupts E2F1-mediated Wnt signaling and GSK3B interacting protein activity, resulting in suppressed endothelial proliferation [111]. Conceivably, the genetic models reinforce the pro-angiogenic activity of PPARγ in endothelial cells.

In short, PPARα and PPARβ/δ exert anti- and pro-angiogenic activities in the endothelial cells of TME, respectively. On the other hand, opposing roles have been reported for PPARγ in angiogenesis. The roles of each PPAR isotype in angiogenesis are summarized in Figure 4. Notably, most findings on PPARγ are not established using oncogenic models. As the physiological cues in a TME are different from a normal condition, the true nature of PPARγ in cancer angiogenesis and tumor epithelium-endothelium crosstalk requires further investigation.

Autocrine signaling facilities self-stimulation, while paracrine signaling allows local cell–cell communication. In the TME, both forms of cell signaling are imperative to coordinate every stage of oncogenesis, alerting the tumor cells how and when to proliferate, evade immune surveillance, escape from the existing microenvironment, and settle at a distal site. The transmission of complex messages in response to cellular stimuli is made possible by a plethora of secretory mediators, including cytokines, chemokines, growth factors, catalytic proteins, miRNAs, extracellular vesicles, and lipid compounds [113]. Many of these messengers are directly or indirectly regulated by PPARs (Figure 5). For instance, a new PPARγ agonist, CB13, remodels the exosomal contents from radio-resistant non-small cell lung cancer to promote endoplasmic reticulum stress and cell death via a PERK-eIF2α-ATF4-CHOP axis [114].

Only a handful of studies have investigated stromal PPAR activities on metastasis, and the results are conflicting. In myeloid-derived suppressor cells (MDSCs), deficiency of lysosomal acid lipase (lal^−/−) impaired the production of PPARγ ligands, which led to reduced PPARγ activity, ROS accumulation, and mTOR-mediated tumor metastasis [158]. Following intravenous injection of B16 melanoma cells, increased lung metastases were observed in mice with myeloid-specific PPARγ knockout, further reinforcing the role of MDSCs’ PPARγ in metastasis. Contradictorily, a PPARγ agonist, pioglitazone, has been shown to promote alternative activation of macrophages in the TME [159]. These pro-tumorigenic myeloid cells can synthesize TGFβ1 to promote EMT of surrounding tumor cells [160]. Although the true role of stromal PPARγ in metastasis remains debatable, a recent study showed that astrocytes liberate polyunsaturated fatty acids, which are PPARγ agonists, to promote the extravasation of circulating cancer cells into the brain while PPARγ antagonists can reduce brain metastatic burden in vivo [161]. Astrocyte–cancer cell communication is also mediated by TGF-β2 and ANGPTL4, the latter of which is an effector of PPARs [162]. Hence, PPARγ may serve as a nutritional cue to provoke the invasion of metastatic cells into a nutrient-rich environment. The results also argue for the potential use of PPARγ blockade to treat brain metastasis.