Cancer-associated fibroblasts in tumor initiation and progression:

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Chronic inflammation in tumor initiation and progression:

Chronic inflammation is one of the hallmarks of cancer [324]. Indeed, 25% of human malignancies are related to chronic inflammation [325]. As early as 1863, the pathologist Virchow recognized chronic inflammation as a pre-condition of tumorigenesis (the “chronic irritation theory”).
It is nowadays well described that malignant tumors preferentially develop at sites of chronic injury. Chronic viral hepatitis, gastric inflammation due to Helicobacter Pylori, as well as inflammatory bowel diseases significantly increase cancer risk. Moreover, tumors usually recur in healing resection margins [326]. Besides, some compounds classified as tumor promoters act as inducers of inflammation: they activate pre-malignant dormant lesions and induce the angiogenic switch [327].
One of the earliest evidence that suggests a connection between wound healing, chronic inflammation and cancer comes from tumors induced by the Rous sarcoma virus. In chickens, this virus generates tumors only at the sites of injection. However, mechanical injuries inflicted on different sites to injected animals or administration of pro-inflammatory factors trigger tumor development at the wounded or treated sites. Conversely, the administration of anti-inflammatory drugs prevents tumor development [328]. The link between chronic inflammation and tumor development is also clearly shown by the generation of dermal fibrosarcomas upon wound healing in mice overexpressing the oncogene Jun [329].
The connection between tumorigenesis and inflammation orchestrates tumor initiation and progression. Both extrinsic and intrinsic pathways mediate it (Figure 8). Chronic inflammation contributes to tumor initiation inducing epigenetic changes and the angiogenic switch through ROS or inflammatory mediators release. On the other hand, tumor progression is mainly fueled by pro-survival signals derived from inflammatory cytokines and chemokines [330]. Extrinsic pathways are activated by external infectious stimuli that increase the risk of cancer. Intrinsic pathways are triggered by mutations leading to proto-oncogenes activation, tumor suppressors inactivation and chromosomal rearrangements. All these events cause the activation of transcriptional factors like NF-κB, STAT3, hypoxia-inducible factor 1 (HIF1), and the secretion of proinflammatory cytokines that recruit inflammatory cells creating a pro-tumorigenic microenvironment [330]. In particular, NF-κB is a key orchestrator of chronic inflammation. It promotes the secretion of pro-inflammatory mediators that sustain tumor growth, survival, and vascularization [327] and regulates adhesion molecules and proteolytic enzymes involved in cancer migration and invasion [331].
The main inflammatory cell population responsible for chronic inflammation is represented by neutrophils [332]. Their deleterious contribution in tissue repair consists of perpetuating the inflammatory response by releasing toxic molecules like ROS that additionally damage cells at the wounding site [333]. Together with neutrophils, macrophages secrete mediators that foster chronic inflammation, including ROS and reactive nitrogen species [326]; besides, they promote cancer cell invasion by producing MMPs and ECM breakdown [205]. Sustained release of toxic mediators by inflammatory cells induces DNA damage and modifies the activity of proteins involved in DNA repair, cell cycle checkpoints, and apoptosis. Indeed, at a molecular level, genomic instability promoted by ROS consists in the repression of genes that mediate mismatch repair and in the inactivation of mismatch repair enzymes [334, 335]. Moreover, NF-κB activation induced by inflammatory cytokines inhibits p53-dependent genome surveillance and induces cytidine deaminase (AID) overexpression, promoting genomic instability by increasing mutation probability during DNA repair [334].

Since several pathways involved in the pathogenesis of fibrotic diseases and cancer

Extensively overlap, therapeutic strategies that tackle the two concomitant diseases appear as an appealing option. In this light, I will summarize the most recent options tested in preclinical or clinical development with a dual therapeutic efficacy on fibrosis and cancer.
Aberrant kinase activity is recognized to contribute to the pathogenesis of neoplastic and fibrotic disorders. Indeed, protein kinases activate downstream signaling cascades involved in cell growth, proliferation, survival, differentiation, etc. Targeted therapies based upon selective kinase inhibition have shown a remarkable efficacy. Imatinib, a BCR-ABL1 inhibitor representing the first success of targeted medicine, revolutionized the treatment of chronic myeloid leukemia. However, it has also shown promising results for the treatment of fibrotic disorders like nephrogenic systemic fibrosis [366] and gastrointestinal stromal tumors [367] via c-KIT and PDGFR inhibition. Recently, the new generation of BCR-ABL1 inhibitors has been approved for the management of scleroderma and systemic sclerosis [368, 369]. In parallel, Sunitinib, another PDGFR inhibitor, has shown clinical efficacy in a large number of cancers and in radiation-induced pulmonary fibrosis [370].

Melanoma heterogeneity:

Tumor heterogeneity is defined as the presence of subpopulations of cells endowed with different phenotypes and behaviors within the same tumor (intra-tumoral) or between tumors of the same subtype within a patient (inter-tumoral) or between patients (interpatient). Genomic, epigenomic, transcriptomic, and proteomic features define tumor subpopulations [464, 465]. Melanoma is one of the best models to observe tumor heterogeneity: practical examples can be macroscopically seen in melanomas that consist of radial and vertical growth components [466, 467] and in metastases deriving from the same primary tumor that show signature variations [468]. Three models to describe tumor heterogeneity have been proposed: the genetic intratumor heterogeneity model, the stem cell model, and the phenotypic plasticity model [464, 465].
Genetic intratumor heterogeneity (ITH): Genetic ITH is caused by replication errors, UVinduced mutagenesis, defective DNA damage repair, telomere alterations, and defects in chromosome segregation [469]. In this model, the progressive acquisition of genetic mutations contributes to phenotype alteration and malignant potential [464]. High genetic ITH is linked to poor prognosis because Darwinian-like selection of clones during tumor progression favors therapy-resistant or metastatic-prone subclones [470]. Importantly, in the genetic ITH model, the molecular changes that trigger tumor heterogeneity are irreversible [464, 471] and the outcomes deriving from genetic diversity may vary depending on specific external signals. Hence, the same genetic variant can confer advantages or disadvantages to the tumor subpopulations depending on the context [472]. Therefore, although it is essential, the genetic ITH is not sufficient to explain melanoma progression and therapy resistance.

Intrinsic resistance:

Intrinsic (or innate) resistance indicates a pre-existing drug resistance that concerns the entire cancer cell population or some subpopulations, and it exists before the exposure to the drug. Intrinsic resistance is usually presented by cells that do not harbor the targeted mutation or are not dependent on the inhibited pathway. On the contrary, acquired resistance refers to a tumor that initially responds but relapses and progresses later [464]. However, it is generally difficult to distinguish between intrinsic and acquired resistance because subpopulations intrinsically resistant may become enriched due to drug exposure. In this case, an initial response is observed, followed by relapse [464].
Innate resistance to BRAF inhibition is observed in 50% of patients with BRAF-mutant melanoma: 15% of patients show no tumor shrinkage while 35% of patients get a degree of tumor shrinkage that is not sufficient to meet the RECIST criteria for a partial response [597]. In BRAF-mutant melanoma, the root cause of innate resistance to targeted therapies can be identified on additional genetic mutations.
A study about a 26-years old patient with primary BRAFV600E mutant melanoma refractory to Vemurafenib reveals that five different sites of disease analyzed by whole genome sequencing and SNP array analysis present BRAFV600E mutation and Q209P mutation in the GNAQ gene, including pre-treatment specimens. This mutation triggers sustained ERK activation conferring resistance to BRAF inhibition. Moreover, PTEN loss is identified as another early founder event. Indeed, its deletion is identified in the five disease sites and activates the AKT survival pathway [598].

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Genetic mechanisms of acquired resistance:

Acquired resistance is traditionally defined as the genetic evolution of cancer in response to therapeutic pressure. Genetical evolution consists of acquiring specific genetic alterations like mutations, gene amplification, gene deletions, and chromosomal alterations that confer clonal advantages to cancer cells, enabling them to escape the therapeutic challenges. This view reflects the Darwinian selection theory, for which cells carrying specific mutations are selected by therapeutic pressure over time. Genomic evolution can be pictured as branching when divergent subclones emerge or as linear in case of sequential acquisition of mutations.
Analysis of tumors from relapsed patients reveals that in 80% of cases resistance to monotreatment with BRAF inhibitors is due to reactivation of the MAPK pathway and sustained ERK signaling [618]. Common genetic mechanisms leading to MAPK pathway reactivation act upstream of BRAF and include NRAS amplification, NRAS activating mutations, and loss of the MAPK pathway negative regulator NF1. Besides, overexpression of different RAF isoforms triggers resistance by direct activation of MEK [619]. Downstream of BRAF, amplification or mutations of MEK and MEK activators trigger MAPK reactivation.
Moreover, genetic changes affecting BRAF, including allele amplification or splice variants, contribute to MAPK pathway reactivation and they are found in up to 30% of patients with acquired resistance to BRAF inhibition [620, 621]. However, when the resistance is triggered by MAPK pathway reactivation, combination of BRAF and MEK inhibitors provides clinical benefits ameliorating the patient outcome.
Together with MAPK pathway reactivation, genetic alterations in the PI3K-PTEN-AKT axis are responsible for relapse in 22% of patients. Augmented PI3K signaling is due to PTEN loss of function by mutations or deletions in 10% of melanomas [620, 622]. Notably, specific genetic defects in these two key signaling pathways coexist in the same tumor or multiple tumors from the same patient.

Non-genetic mechanisms of acquired resistance:

Phenotype plasticity consists in the adaptive responses that occur in melanoma cells upon exposure to environmental insults. These phenotypic transitions take also place upon the therapeutic treatment, driving cancer cells toward the acquisition of resistance. Hence, the dissection of the several non-genetic pathways of resistance put in place by melanoma cells can pave the way to new promising therapeutic avenues to eradicate the multiple processes that concur to resistance acquisition (Figure 13) [465, 625]. Adaptation of melanoma cells to the challenges imposed by MAPK inhibitors (MAPKi) leads to the emergence of distinct cell populations. In up to 78% of melanoma patients, the initial response to MAPKi therapy consists in the increase of melanocytic differentiated MITFhigh cells that provide a drug-tolerant state thanks to the MITF-mediated survival pathways counteracting the cell death induced by the targeted therapy [535, 626, 627]. In parallel, cell populations characterized by a progressively more dedifferentiated phenotype co-emerge. These cells display an invasive or neural crest stem cell-like signature and have an increased expression of several receptor tyrosine kinases (RTKs) like NGFR [535, 536], PDGFR [628], IGF1R [629], EGFR [630], AXL [534, 613, 614]. Hyperactivation of the mentioned RTKs ensures pro-survival signalings independent from the MAPK pathway. This cell-state also correlates with the loss of MITF and its upstream regulators SOX10 or PAX3 [547, 630]. Accordingly, around 70% of relapsed melanomas show an increased expression of AXL [631] and 50% of relapsed melanoma shows a reduced expression of MITF [626]. However, upregulated MITF expression can be found in relapsed tumors and may be due to MITF gene amplification, as previously mentioned.

Table of contents :

LIST OF ABBREVIATIONS
LIST OF FIGURES AND TABLES
INTRODUCTION
I. Fibrosis and cancer
1) Myofibroblasts in wound healing and fibrosis:
Wound healing:
Fibroblast to myofibroblast transition:
Myofibroblasts origin:
Pathogenesis of fibrosis:
-Cell-autonomous mechanisms: activation of pro-fibrotic signaling pathways
-Non-cell-autonomous mechanisms: the extracellular matrix as a driver of fibrosis
2) Cancer as an over-healing wound:
a) Molecular and cellular composition of the tumor microenvironment:
Myofibroblasts in cancer: cancer-associated fibroblasts definition and origin
Cancer-associated fibroblasts in tumor initiation and progression:
d) Targeting cancer-associated fibroblasts as a therapeutic strategy:
Chronic inflammation in tumor initiation and progression:
Anticancer therapy-induced fibrosis:
Anti-fibrotic therapies in the treatment of cancer:
II. Melanoma
1) Epidemiology:
2) Risk factors:
a) Genetics of melanoma:
b) Environmental factors:
3) Origin
a) Melanocytes:
b) Melanomagenesis:
c) Driver mutations:
d) Melanoma heterogeneity:
4) Clinical management:
a) Targeted therapies:
b) Immunotherapies:
5) Resistance to MAPK-targeted therapies:
a) Intrinsic resistance:
b) Genetic mechanisms of acquired resistance:
c) Non-genetic mechanisms of acquired resistance:
-Cell-intrinsic mechanisms of resistance:
-Cell-extrinsic mechanisms of resistance:
1) Therapy-induced fibrotic remodeling of the tumor microenvironment: .
2) Therapy-induced cytoskeleton remodeling:
3) Therapy-induced inflammation:
III. microRNAs
1) Non-coding RNAs:
a) Definition and classification:
b) miRNAs nomenclature:
2) Biogenesis
a) Transcription
b) Maturation
3) Mechanisms of action:
4) MiRNAs-based therapies:
a) miRNAs inhibition:
b) miRNAs replacement:
c) miRNAs as diagnostic and prognostic biomarkers:
5) MiRNAs in fibrosis: fibromiRs
6) MiRNAs in cancer: oncomiRs
a) MiRNAs in melanoma:
b) MiRNAs and melanoma resistance to MAPK-targeted therapies:
7) The miR-143/145 cluster: a profibrotic locus with a controversial role in cancer .
a) Structure, conservation, expression regulation:
b) miR-143/145 cluster in fibrosis
c) miR-143/145 in cancer:
-Molecular targets of the cluster in cancer:
RESULTS
I. Research context and aims:
II. Scientific article
DISCUSSION
CONCLUSIONS
AND PERSPECTIVES
BIBLIOGRAPHY 

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