3.2.1　Cancer-associated Fibroblasts (CAFs)

The term CAFs refers to two distinct sub-populations of fibroblasts: cells similar to resident fibroblasts and myofibroblasts.Fibroblast can be activated through several conditions including growth factors, direct cell-cell communication, adhesion molecules, contacting with leukocytes,reactive oxygen species and microRNA.After activation fibroblasts are known as CAFs that,differently to normal fibroblast, are perpetually activated, do not return to a normal phenotype, do not undergo apoptosis, and promote cancer progression.CAFs have an important role in tumor growth because they stimulate angiogenesis, cell proliferation, invasion, and motility by releasing growth factors and cytokines, by deregulating Notch and p53 signaling pathways, and by producing metalloproteinases (MMPs).CAFs may affect ECM stiffness at primary tumors, enhancing cancer cell invasion favouring metastatic spread by inducing epithelial to mesenchymal cell transition(EMT).They also regulate immune response because they express intercellular adhesion molecule 1 (ICAM1) and programmed cell death protein 1 ligand 1 (PDL1) and PDL2, which mediate immunosuppressive functions [30].(https://www.daowen.com)

Different strategies are being tested to overcome the resistance of drugs to access to tumor stroma and are directed against CAFs and pathway activated by these cells.In metastatic pancreatic adenocarcinoma (mPADC) the presence of a CAF-rich stroma is suspected to create chemo-resistance.A combination treatment of nab-paclitaxel (Abraxane) and gemcitabine normalizes the amount of CAFs compared to gemcitabine alone in patients with mPADC improving overall survival, progression-free survival and response rate.Other therapeutic strategies consider the employment of drugs fizzling out signaling pathway activated by cancer cells and CAFs.An example of antitumor environment drug is nindetanib or BIBF1120 having tyrosine kinase inhibitor activity towards receptors of VEGF, FGF and PDGF, and is actually registered as second line therapy for non-small-cell lung cancer (NSCLC) in combination with docetaxel.Anti-TGF-β therapies have also been evaluated in cancer treatment because they interfere with different components of the tumor environment.Fresolimumab, a monoclonal antibody against TGF-β has been tested in phase I and II clinical trials for melanoma, renal cell carcinoma and malignant pleural mesothelioma (MPM).Reversible cutaneous keratoacanthomas/squamous cell carcinoma and hyperkeratosis were reported as major drug-related adverse events due to the immune suppressor function of this drug towards normal epithelial cells.In a phase II study conducted on MPM patients, Fresolimumab did not show any radiographic response, but a 12 months median survival was interesting and it opens the way to study Fresolimumab in combination with immunological agent for its immune regulation function.Another monoclonal antibody against TGF-β, Galunisertib (LY2157299 monohydrate), is under evaluation in phase Ib and II in patients affected by neurological, hepatocellular and pancreatic malignancies [31, 32].