No abstract

The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression.Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological responses were inhibited by DDR1 silencing and enhanced by DDR1 overexpression.Experiments in mouse fibroblasts co-transfected with the human IGF-IR and DDR1 gave similar results and indicated that, in the absence of IGF-IR, collagen-dependent phosphorylation of DDR1 is impaired.These results demonstrate a critical role of DDR1 in the regulation of IGF-IR action, and identify DDR1 as a novel important target for breast cancers that overexpress IGF-IR.

The genetic profile of PTC changed over the last 15 yr, with a significant decrease in the prevalence of RET/PTC rearrangements and an increase in BRAF(V600E) mutations. In addition, the mean age at diagnosis increased and tumor size decreased over the study period.

Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer.In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF-I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 upregulation required the activation of the PI3K/AKT pathway while the ERK1/2, the p70/mTOR and the PKC pathways were not involved. Moreover, we observed that DDR1 protein upregulation was induced by translational mechanisms involving miR-199a-5p suppression through PI3K/AKT activation. This effect was confirmed by both IGF-II produced by cancer-associated fibroblasts from human breast cancer and by stable transfection of breast cancer cells with a human IGF-II expression construct. Transfection with a constitutively active form of AKT was sufficient to decrease miR-199a-5p and upregulate DDR1. Accordingly, IGF-I-induced DDR1 upregulation was inhibited by transfection with pre-miR-199a-5p, which also impaired AKT activation and cell migration and proliferation in response to IGF-I.These results demonstrate that, in breast cancer cells, a novel pathway involving AKT/miR-199a-5p/DDR1 plays a role in modulating IGFs biological responses. Therefore, this signaling pathway may represent an important target for breast cancers with over-activation of the IGF-IR axis.

It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments.