Liver systemic failure, portal hypertension, high susceptibility to infection and high risk to develop HCC are the main clinical consequences of cirrhosis 28 , Interestingly, multiple clinical reports have reported that liver insult eradication can regret liver fibrosis in huge number of patients, mostly during the first stages 29 — Figure 2.
Inflammation plays a key role in liver fibrosis development. After injury takes place, infiltration of immune system cells -macrophages, lymphocytes, eosinophils, and plasma cells- arises to the damaged place. Lymphocytes produce cytokines and chemokines, which activate macrophages. Activated macrophages stimulate inflammatory cells such as lymphocyte, among others, over-activating and maintaining the inflammatory environment In this sense, hepatic macrophages have been described as a potential targets against fibrosis 39 , Macrophages represent a heterogeneous cell population with a huge cell plasticity, where diverse microenvironment stimuli polarize them into different phenotypes There are mainly two sources of hepatic macrophages: liver resident macrophages, also called Kupffer cells 42 , and circulating monocytes inflammatory recruited macrophages Besides the origin, both could play significant roles in the development of fibrosis.
Resident hepatic macrophages secrete the chemokine CCL2 a potent chemoattractant in order to recruit monocytes which could increase and promote fibrosis. Although, it was described that the pro-fibrotic functions of these resident macrophages remain functional even when recruited macrophages are pharmacologically inhibited using CCL2 antagonists In the early stages, activated macrophages secrete pro-inflammatory cytokines and produce reactive oxygen species ROS , while in late stages macrophages have been associated with release of anti-inflammatory factors, attenuating inflammation and promoting tissue regeneration 43 , Macrophages are classify into M1, also known as classical or pro-inflammatory; and M2, also known as alternative or anti-inflammatory macrophages 51 , It is not easy to strictly separate both liver macrophage populations, since they could show common gene expression, and even more M2 macrophages are classify also in different subclasses.
For that reason, it has been proposed that could be more adequate to separate them according to their functions: defensive, restorative and regulatory macrophages In the classical classification, M1 macrophages are associated with inflammatory diseases due to microbicidal activity through their capacity to produce ROS and their phagocytic functions , antigen presentation and antitumor activity.
M2 macrophages stimulate an anti-inflammatory environment and promote regeneration and wound healing. Fibrosis-induced model in rats by thioacetamide show that both M1 and M2-macrophagues polarizations occur during development of the disease Current data seems to indicate that both hepatic and recruited macrophages play relevant roles in the progression and reversion of liver fibrosis.
Targeting both and the reorientation of their phenotypes are arising as attractive therapies In the liver, the most fibrogenic MFB are endogenous and their origin is controversial and still unclear, but nowadays there are accepted different sources 63 — 65 , among them, portal and resident fibroblasts 66 , activation and differentiation of HSC more details in the next section 16 , 67 , bone marrow-derived fibrocytes 68 , liver epithelial cells hepatocytes and cholangiocytes that undergo EMT 69 — 71 , endothelial cells that undergo EndMT 66 , 72 , vascular smooth muscle cells and pericytes EMT-clear example of cellular plasticity- is a process that drives a de-differentiation of epithelial cells to a mesenchymal-like phenotype increasing their migratory and invasive properties 13 , 14 , 74 , The reverse process is called as MET and allows cells to differentiate into different organs and tissues.
In a tumorigenic context, mesenchymal migratory tumor cells undergo MET to metastasize Partial EMT is described for cells that co-express both epithelial and mesenchymal markers. Even more, EMT is classified into different subclasses related with the biological context 78 : Type 1 EMT is involved in development stages; type 2 EMT concerns regenerative process and organ fibrosis; and type 3 EMT is related with metastatic process.
During liver fibrosis, type 2 EMT plays a relevant role in the appearance of a pro-fibrotic fibroblast phenotype. Bipotent adult hepatic progenitor cells, which possess the cell plasticity to differentiate into hepatocytes and cholangiocytes after different stimuli 79 , are able to undergo EMT in response to liver injury during cholestatic liver fibrosis.
Hepatocyte plasticity could play relevant roles during the progression of chronic liver diseases. Indeed, hepatocyte-derived fibroblasts are an additional and significant lineage of mesenchymal cells that contribute to progression of liver fibrosis. HSC are characterized by the store of vitamin A, lipid droplets and the expression of a large number of adipogenic genes and neural markers.
After liver insults, different paracrine and autocrine signals are triggered promoting the HSC activation -transdifferentiation- from a quiescent state to an activated myofibroblastic phenotype.
This provokes the progressive scar formation and the development of liver fibrosis 29 , HSC activation is one of the most important steps during liver fibrosis and is mediated by different signals, such as growth factors PDGF and CTGF, among others , lipidic mediators, as well as ROS and cytokines produced by hepatocytes, cholangiocytes, endothelial cells, macrophages Kupffer cells and immune cells 67 , Mild to moderate liver fibrosis may be reversible.
The reversion process is related with the elimination of the damaging stimuli. During liver fibrosis reversion, activated HSC or myofibroblast reverted to an inactivated phenotype. In both normal physiological and pathological conditions, ROS are critical intermediates. Oxidative stress plays a role during both initial inflammatory phase and its progression to fibrosis ROS may be generated in the liver by multiple sources, including the cytochrome p family members, peroxisomes, mitochondrial respiratory chain, xanthine oxidase, and nicotinamide adenine dinucleotide phosphate NADPH oxidases.
NOX enzyme family generate ROS, either hydrogen peroxide or superoxide as the primary species, during oxygen catalytic metabolism for arrange of signaling functions and host defense. Liver cells either parenchymal and non-parenchymal express different members of the NOX family. NOXs proteins could be playing relevant roles during liver fibrosis development , In in vivo models of liver fibrosis, the levels of NOX4 are up-regulated, as well as in patients with chronic hepatitis C virus derived infection, increasing along the fibrosis degree.
In this sense, apoptotic hepatocytes after liver injury generate apoptotic bodies which were described to promote HSC survival HCC is a major public health problem worldwide with almost , new cases each year and its incidence is increasing in Europe and worldwide. In reports from World Health Organization, liver cancer is the second leading cause of cancer-related deaths, following lung cancer HCC is the most common primary liver malignancy in adults. Intriguingly, there are significant differences on the incidence when considering the gender, being the male to female ratio estimated to be 2.
This difference is mainly attributed to the different exposition to risk factors, as well as the influence of androgens and oestrogens on HCC progression Exposition to risk factors also determines the incidence of liver cancer regarding age or ethnicity and the highest incidence of HCC is found in Asia and sub-Saharian Africa — In most cases, HCC develops within an established background of chronic liver disease.
Progressive hepatic fibrosis frequently evolves to cirrhosis, which is the largest risk factor for developing liver cancer. During hepatocarcinogenesis, a complex multistep process, many signaling cascades are altered as a result of genetic and epigenetic changes that contribute to a heterogeneous molecular profile. Furthermore, cellular plasticity increases the complexity of the cellular heterogenicity.
Indeed, tumor heterogeneity in HCC is impressive: it can be observed between patients, between nodules in the same patient i. Many molecular mechanisms are known to be clearly involved in HCC Signaling pathways are related mainly with cell proliferation, angiogenesis, invasion, and metastasis. The role of the microenvironment in tumor initiation and progression in HCC is critical and HCC cells could acquire an abnormal phenotype due to tissue remodeling altering their biological behavior , Of relevance, this study also discriminated HCC cell lines by degree of invasiveness.
Interestingly, the early response pattern is associated with longer, and the late response pattern with shorter, survival in human HCC patients.
Figure 3. Neoplastic transformation of hepatocytes and progenitor cells, which both are epithelial-like, to a mesenchymal-like phenotype boost heterogeneity in HCC After liver insult, non-transformed hepatocytes can undergo EMT as an adaptative response to move and scape from damaged, inflammatory, hypoxic and redox-activated microenvironment allowing them to find better conditions Upon HCC development, the excessive growth of transformed cells also generates hostile nodules for cancer cells due to oxygen depletion in internal areas hypoxic environment as compared to tumor stroma borders, which induces tumor cell necrosis.
The variability in the prognosis of HCC patients suggests that it may comprise several distinct biological phenotypes, but individuals with HCC who shared a gene expression pattern with fetal hepatoblasts showed to have a poor prognosis It is suggested that the expression of stem-related genes could also be mediating the acquisition of an EMT phenotype. In this sense, the stem-related CD44 or CD are not only involved in the acquisition of stem properties, but also in the switch to a more mesenchymal, migratory phenotype , Moreover, intermediate EMT states have recently been identified as crucial drivers of organ fibrosis and tumor progression During partial-EMT stage, both epithelial and mesenchymal stem genes can be expressed.
CSCs could contribute to the failure of therapies to abolish malignant tumors. In pre-clinical assays, cancer stem-like spheres from de-differentiated HCC-derived cell lines show increased expression of stemness markers CD44 , and higher resistance to anticancer drugs Furthermore, the acquisition of some mesenchymal properties and the expression of CD44 impair the HCC cell response to sorafenib-induced apoptosis For this, novel strategies are focused to target CSC development.
The combination therapy revealed an advantage in terms of overall survival and time to progression. Mesenchymal-related gene expression was decreased in resminostat-treated HCC cells.
This event is concomitant with an epithelial-related gene expression increase, more organized tight junctions and lower invasive growth. Indeed, resminostat down-regulated CD44 expression is coincident with a decrease in the stemness properties.
M2-like macrophages are major players in the connection between inflammation and cancer, involved in functions such as: promotion of tumor cell proliferation, ECM turnover, inhibition of adaptive immunity, among others , , TAMs are correlated with angiogenesis, metastasis, and poor prognosis , Accumulating evidence indicates that the immune system microenvironment plays key roles in the development of HCC , Treg cells -Foxp3-positive cells- are involved in immune homeostasis, peripheral tolerance and prevention of autoimmunity , These peptide inhibitors were proved to be also useful in enhancing the efficacy of antitumor immunotherapy To increase the delivery efficiency, in a recent study, one of these peptides P was loaded separately into folic acid-functionalized nano-carriers made of bovine serum albumin.
Cellular studies demonstrated the targeting efficiency of the hybrid carriers Despite limited antiproliferative effects, Galunisertib yielded potent anti-invasive properties in HCC models and in ex vivo tumor tissue samples from patients Worthy to note, in combination, Galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis.
Galunisertib also reduced the expression of stemness-related genes, such as CD44 and THY1, in vitro and in ex vivo human HCC specimens, overcoming stemness-derived aggressiveness Recent studies have also suggested the potential efficiency of Galunisertib as antifibrotic drug. In ex vivo studies, using both healthy and cirrhotic human precision-cut liver slices, Galunisertib reduced fibrosis-related transcription, which correlated with a significant inhibition in the production and maturation of collagens Some efforts are being made in optimizing the delivery of Galunisertib in form of novel polymeric nano-micelles, to avoid acidic pH of gastrointestinal tract, colon alkaline pH and anti-immune recognition Once it is proven the safety and the benefit of using Galunisertib in HCC, biomarkers will be extremely useful in the proper selection of patients who might benefit from receiving the drug.
These target genes identified may also serve as biomarkers for the stratification of HCC patients undergoing treatment with Galunisertib. Since biopsy is not frequent in HCC patients, new areas of research must be focused on the improvement of liquid biopsies in these patients to develop the possibility that this kind of analysis may be done in tumor circulating cells.
Despite all current knowledge, there are still many gaps that need to be clarify. Both authors equally contribute to the writing and revision of this work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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