IPF is a proliferative disorder affecting the lungs, characterized by aberrant deposition of ECM and consequent remodeling associated with the activation of fibroblasts as a response to still unknown injuries. IPF diagnosis is confirmed by histological identification of the usual interstitial pneumonia (UIP) pattern on surgical (and rarer transbronchial) biopsies, together with detection at high resolution (HR) computerized tomography (CT) scan of bibasilar reticular abnormalities (honeycombing pattern) with minimal or absent ground-glass opacities [
1,
101,
102]. The key histological feature of IPF is represented by the so-called
fibroblast foci (
FF) defined as aggregates of actively proliferating fibroblasts and myofibroblasts. Activated fibroblasts express α-SMA (smooth muscle actin), accounting for to term “myofibroblasts”. In addition they secrete increased levels of ECM-degrading proteases (metalloproteinases MMP2, MMP3, MMP9), facilitating increased ECM turnover and altered ECM deposition; they also secrete growth factors (such as HGF, IGF, NGF, WNT1 and EGF) which can induce proliferative signals within adjacent epithelial cells. Moreover activated fibroblasts behave as modulators of the immune response following tissue injury by secreting cytokines (e.g. IL-1) and chemokines (e.g. MCP1) [
103‐
107]. Activated fibroblasts/myofibroblasts can be found in wound healing processes and sclerosing tissue and as well as in cancers [
108]. Through embryogenesis, cells start to move out from developing tissues in order to organize the structure of fetal organs. In a similar fashion, in adult life, during wound healing and tissue repair processes, health cells migrate into the wound to recreate pre-existing tissue patterns [
109]. The acquisition of cell motility is required but is not enough to sustain the whole process. Indeed cells need to trigger a number of biological programs, as well as to activate mitotic divisions to repair injured tissues [
110]. Thus embryogenesis, tissue repair after wound healing and cancer share similar mechanistic basis, since the same biological activities—cell proliferation, survival and migration, namely the Invasive Growth—are activated in both normal and malignant contexts. During wound healing repair activities as well as in cancer metastatic spreading, several cytokines are secreted in the reactive interstitial compartment. For instance interleukin-1 (IL-1) and 6 (IL-6), tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β) are known to induce the transcriptional up-regulation of HGF (in fibroblasts and macrophages) and MET (in epithelial cells) [
111,
112]. HGF is also biologically activated, as demonstrated by the overexpression of proteases involved in pro-HGF activation [
113,
114]. Moreover, HGF might be activated through an autocrine loop in stromal myofibroblasts. This mechanisms has been well demonstrated during tumor cell invasion [
115] but can reasonably be significant in wounds repair as well. Overall, this highly performant HGF assures a proper activation of MET, which is, thus, involved in tissue protective physiological systems. These morphogenetic pathways trigger the EMT by activating biological processes such as cell motility and invasion [
116], known as invasive growth program. The aberrant activation of the above described wound healing machinery ultimately characterizes IPF onset and progression. Thus, HGF/MET-driven aberrant morphogenesis plays a crucial role not only in cancer but in IPF, as well. However it should be underlined that its activation and progression in IPF certainly differs from that in cancer, regarding both spatial and temporal characteristics. A proliferating tumor becomes malignant when neoplastic cells move to adjacent environments and settle in tissues and organs that are distant from the original site of growth. In IPF the actively proliferating FFs contrast with neighboring areas of relatively normal parenchyma and move from subpleural regions towards central areas. IPF is overall a lung-specific disease, defined by a centripetal track of disease progression in absence of distant cell scattering. The latter is a key difference with respect to scattering of malignant cells, which essentially means distant and peripheral dissemination. Furthermore IPF is a heterogeneous disease also in the age of lesions, meaning the stage of pathology in different lung parenchymal regions. Thus normal lung tissue is interspersed with interstitial fibrosis, honeycomb cysts and fibroblast foci [
1]. On the other hand, it is well known that most tumors tend to become more aggressive in clinical behavior over time, although this time course may be variable. During cancer progression, MET activation generally occurs as a late event, as a consequence to transcriptional up-regulation driven by unfavorable microenvironmental conditions, such as hypoxia or ionizing radiation [
7,
117]. Sometimes, rapidly invasive cancers are diagnosed because of appearance of metastatic lesions in absence of a clearly detectable primary mass. Among these highly invasive and malignant tumors, an extremely high mutational frequency of
MET coding sequence has been reported;
MET mutations have been biologically associated to the observed transformed phenotype [
118]. The above described differences between IPF and cancer strictly reflect the differences of cell lineages. Indeed cancer is, by definition, a disease of genes, which evolves through a dynamic process of clonal expansion and selection in of advantageous somatic driver lesions [
119,
120]. Each individual tumour is defined by a unique clonal evolution resulting from an intricate connection between genetic and non-genetic/epigenetic factors, leading to phenotypic and genotypic heterogeneity. Among the diversity in tumor-cell population, the CSC compartment brings about tumor maintenance and progression [
121]. MET-driven invasive growth is aberrantly activated in cancer, mainly as a late event, leading to distant dissemination and malignant progression. More recent studies have reported that MET amplified cancer clones are selected under therapeutic pressure in a context of molecularly heterogeneous lesions exposed to targeted therapies or radiotherapy [
8,
122‐
125]. In CSC, both the occurrence of genetic lesions (as amplification) and physiological expression of MET can contribute to tumorigenesis and therapeutic resistance, by sustaining the invasive growth phenotype. On the other hand, myofibroblasts within FF in IPF are characterized by cellular and genetic heterogeneity. Notably—very recently, Jones and colleagues elegantly demonstrated that FFs in IPF identify—quite unexpectedly—morphologically complex 3D-structures, each independent from the others [
126]. These findings strongly suggest that IPF onset relies on the aberrant local responses that are activated and lead to multifocal injuries. As a consequence diffuse cellular fate conversion and tissue plasticity are associated to IPF. During organ regeneration, MET physiological activation displays protective functions: epithelial cells located at the wound edges exploit invasive growth to enhance cellular division and repopulation of the injured areas [
127‐
129]. When the damage inappropriately persists, as in IPF, the HGF/MET pair actively contrasts myofibroblasts activation and the consequent associated abnormal deposition of extracellular matrix [
130]. Moreover it is well known that semaphorins might activate MET in and HGF-independent manner. As already presented, MET and plexins share high homology at the extracellular sema domain. When MET oligomerizes with plexins, it can be activated by semaphorins, even in the absence of its ligand HGF [
131,
132]. Growing evidence sustains that semaphorins—and their ligands plexins—have a role in enhancing immune function and angiogenesis as well as in controlling lung fibrogenic diseases [
133‐
136]. As a consequence, fibrosing settings, as IPF, which co-express both HGF and plexins might feature even hyperactive invasive capacities.