As described in the previous sections, the TGFβ signaling pathway plays important roles in wound healing and fibrogenesis through its cross talk with other signaling pathways and diverse mediators. TGFβ-induced EMT and accumulation of myofibroblasts can be promoted by integrin-dependent activation of SMAD and Wnt/β-catenin signaling [103]. Myofibroblasts are resistant to apoptosis, which promotes fibrogenesis, partly through reduction of the anti-fibrotic prostaglandin E2 (PGE2) in IPF [104]. The features of these phenomena that lead to EMT appear to be similar to those of tumor cells, and myofibroblasts promote cellular infiltration and progression through multiple mediators in a tumor environment.

The Wingless-type protein (Wnt) family, which consists of 19 secreted proteins, transmits its signal through activation of multiple pathways. One major Wnt pathway, termed the canonical pathway, inhibits GSK3β, leading to the stabilization and accumulation of β-catenin in the cytosol and its translocation into the nucleus, consequently resulting in enhanced expression of target genes that are associated with diverse diseases. As described in the previous Sect. 14.3.1, the Wnt/β-catenin pathway is one target of TERT regulation. β-catenin transmission of Wnt signals to the nucleus regulates diverse oncogenic genes including cyclin D1 and cMYC, and its overexpression and stabilization can promote oncogenesis. The review by Stewart et al. indicates that expression of WNT1, a Wnt ligand, is correlated with aberrant β-catenin expression and increased expression of cMYC, cyclin D1, VEGFA, MMP7, Ki67, and survivin, resulting in proliferation of NSCLC [105]. The other Wnt pathway, termed the noncanonical pathway, which does not involve β-catenin, is mainly comprised of two types of pathways, the planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt/Ca2+ pathway). The combined expression of WNT7A and FZD9 in NSCLC cell lines leads to ERK5 activation, which in turn leads to increased PPARγ expression and activation of Sprouty-4. Sprouty-4 inhibits EMT, consequently inhibiting tumor growth [106, 107]. Indeed, aberrant expression of Wnt ligands and Wnt signaling mediators has been frequently found in NSCLC.

The Wnt/β-catenin pathway also promotes EMT and myofibroblast differentiation that is mediated through TGFβ, thereby contributing to pulmonary fibrogenesis. The Wnt/β-catenin signaling pathway was upregulated in lung tissues of IPF patients. Moreover, β-catenin targets cyclin D1 and MMP7, both of which are considered to be associated with pulmonary fibrogenesis [108].

Phosphoinositide 3-kinases (PI3Ks) regulate cellular proliferation, survival, adhesion, and motility. These kinases stimulate PIP3 synthesis on the cell membrane, thereby promoting the PI3K/AKT/mTOR pathway, a downstream signaling pathway composed of multiple receptor tyrosine kinases. The PI3K/AKT/mTOR pathway is activated early in the pathogenesis of pulmonary tumorigenesis through the modulation of multiple signals as follows, resulting in inhibition of apoptosis and cell survival: (1) mutations in PI3K or PTEN as well as in the EGFR or KRAS and (2) PIK3CA amplification, PTEN loss, or AKT activation [109]. In fibroblasts of IPF, PI3K/AKT/mTOR signals are aberrantly activated, while PTEN activity is lower than that of normal cells [110]. Furthermore, the PI3K/AKT/mTOR pathway interacts with many other signaling pathways, including those of MAPK and VEGFR, in IPF cells [111].

Cross talk between the NFκB and PI3K/AKT/mTOR signaling pathways may contribute to lung cancer cell survival and proliferation [112]. PI3K/AKT promotes NFκB activity in an IKKα-dependent manner [113], while NFκB is activated by Fas-associated death domain protein (FADD) phosphorylation through IKK, thereby promoting proliferation in lung adenocarcinoma [114]. Furthermore, EGF induces IKK-independent NFκB activation through IκBα phosphorylation in lung adenocarcinoma cells [115]. NFκB activation was associated with KRAS mutation, and both lost p53 function and active KRAS ^G12D , the major RAS point mutation in lung cancer, constitutively activate NFκB as well as downstream signaling pathways, such as PI3K and MAPK, in lung cancer cells [116]. NFκB activation is also found in the IPF-associated inflammatory process. NFκB-dependent inflammatory mediators, including tumor necrosis factor (TNF)-α, TGFβ, interleukin (IL)-1, inducible nitric oxide synthase (iNOS), and interferon (IFN)-γ, were highly expressed in IPF patients and in animal models of pulmonary fibrosis [117–119]. Previous in vivo studies showed that suppression of the NFκB signaling pathway can attenuate bleomycin-induced pulmonary fibrosis, while in vitro studies also found that the NFκB signaling pathway contributed to the regulation of TGFβ [119–121].

Fibroblast growth factors (FGFs) are a family of homologous polypeptide ligands that bind to their cognate FGF receptors (FGFRs) [122]. There are 22 FGF ligands comprising six subfamilies and four FGFR isoforms that are differentially activated by FGF ligands in conjunction with the scaffold protein heparan sulfate proteoglycan. Binding of FGF ligands to FGFRs transmits signals associated with angiogenesis as well as with cellular migration and proliferation, and the FGF signaling pathway is involved in the pathogenesis of diverse diseases. However, FGF signaling exerts reciprocal effects on tumor promoting and suppressive activities, which are dependent on the tumor type. Regarding IPF, TGFβ released from AECs induces the proliferation of pulmonary fibroblasts through FGF2, which promotes phosphorylation of p38 MAPK and JNK [123], and high FGF2 levels have been found in the bronchoalveolar lavage fluid and serum of IPF patients [124]. Many NSCLC cells showed elevated FGF2 levels, which in turn promote the growth of these tumor cells by intracrine mechanisms [125]. FGF2 also contributes to angiogenesis and tumor proliferation in many types of cancer, and FGF2-mediated autocrine and paracrine signaling can potently promote oncogenesis.

Another FGF, FGF1, exerts antifibrotic activity through downregulation of collagen expression and antagonization of some TGFβ-mediated profibrotic functions [126]. FGF1 was also shown to restore TGFβ-induced EMT in AECs through dephosphorylation of the SMAD2 phosphorylation that was induced by the MEK/ERK pathway. FGF1-mediated activation of FGFR signaling induces the recruitment and activation of SRC homology (SH2)- or phosphotyrosine (PTB)-containing proteins, thereby activating multiple signaling pathways including PI3K/AKT, MEK1/2-ERK, and p38MAPK [127]. Recently, Daly et al. reported that low levels of FGF1 are associated with favorable outcomes in stage I lung adenocarcinoma [128].

Fas, a cell surface death receptor of the TNF receptor (TNFR) superfamily, paradoxically promotes both survival/differentiation and apoptosis through the modulation of immune responses. Low to absent staining of Fas was detected in fibroblastic cells of fibroblast foci from IPF patients [129]. Exposure to the proinflammatory cytokines, TNF-α and IFNγ, increases Fas expression in an NFκB- and MAPK-dependent manner, thereby sensitizing fibroblasts to Fas-induced apoptosis and reversing the resistance of lung fibroblasts to apoptosis, which is mediated by a prosurvival effect of TGFβ. Aberrant Fas/Fas ligand (FasL) expression is found in many lung cancer cells and samples [130], suggesting its contribution to lung carcinogenesis.

The vascular endothelial growth factor (VEGF) signaling pathway is well characterized. VEGF ligands (VEGFA to VEGFE and placental growth factor) induced by hypoxia, growth factors, and cytokines interact with VEGF receptors (VEGFR1–3), especially with VEGFR2 that activates the PI3K/AKT pathway; promotes cellular proliferation, migration, and survival as well as angiogenesis; and inhibits apoptosis. VEGF is highly expressed in lung cancer, and its expression is associated with poor prognosis [131]. While normal wound healing requires angiogenesis, aberrant neovascularization is often found in IPF tissues, suggesting that VEGF signaling is associated with the development of IPF. Furthermore, Kobayashi et al. showed that SMAD3 signaling mediates TGFβ-induced VEGFA production in human lung fibroblasts [132].

The platelet-derived growth factor (PDGF) family, which consists of PDGFA to PDGFD, promotes cellular proliferation, invasion, and angiogenesis as well as wound healing and proliferation of mesenchymal cells. Enhanced PDGF expression and activation of its signaling have been reported in different types of cancer and in fibrotic disorders. Dimeric PDGFs bind to the receptors PDGFRα and PDGFRβ, thereby transmitting signaling through PI3K, SRC, phospholipase C-γ, and RAS pathways in both an autocrine and a paracrine manner [133]. PDGFA and PDGFC paracrine signaling was associated with fibroblastic tumor infiltration in NSCLC cell lines [134]. Furthermore, PDGF signaling, which partly overlaps with VEGF signaling, activates cancer-associated fibroblasts (CAFs) and recruits VEGF-producing stromal fibroblasts, leading to both tumorigenesis and angiogenesis [135]. PDGF that is synthesized by alveolar macrophages is a potent mitogenic and chemotactic factor for fibroblasts. Previous in vitro studies showed that PDGF interacts with several fibrotic mediators including TGFβ, IL-1, TNF-α, FGF, and thrombin, thereby promoting fibrogenesis. Macrophages and fibroblasts from IPF patients produce PDGF, whereas PDGFB and PDGFR mRNAs are highly expressed in hyperplasic ATII cells in IPF [136]. PDGF/PDGFR signaling can at least partly interact with VEGF/VEGFR and FGF/FGFR signaling pathways, and the intricate cross talk between these pathways may contribute to the common pathogenesis of IPF and lung cancer.

Signaling of the RAS/RAF/MEK/MAPK pathway is one of the most extensively characterized signals and modulates cellular migration, proliferation, and apoptosis; its aberrant signals are therefore involved in the development of diverse diseases. In particular, this pathway is frequently activated in lung cancer, most commonly via KRAS mutations in approximately 20 % of lung cancers, particularly in adenocarcinomas in smokers [137]. The RAS/RAF/MEK/MAPK pathway has also been associated with the development of IPF. Many molecules and pathways, as well as most signals described in this section, can converge, regulate, or interact with the RAS/RAF/MEK/MAPK pathway.

Gap junctions are composed of protein complexes including connexins that characterize cell-cell communication, and their alteration is tightly associated with cellular proliferation, tissue repair, and tumor growth. Vancheri et al. reported the possible role of connexins, especially connexin 43 (CX43), in the common pathogenesis of IPF and lung cancer [138].

Multiple pathways that are mutually dependent interact with one another, thereby regulating the signals that can lead to inflammatory processes and tumorigenesis. Therefore, a possible common pathway of IPF and lung cancer may provide a therapeutic perspective on these comorbid disorders. For example, nintedanib that targets PDGFRα and PDGFRβ, VEGFR1 to VEGFR3, and FGFR1 to FGFR3 has therapeutic potential for both IPF and NSCLC based on the phase III trials, INPULSIS-1 and INPULSIS-2, for IPF and LUME-Lung 1 for NSCLC [139, 140].