Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LA, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo We, et al. 85% [1C5]. In sufferers identified as having indolent or intense B-cell non-Hodgkin’s lymphoma, the usage of the anti-CD20 antibody rituximab provides led to improved success [6]. They are only some of the most regarded examples of the breakthroughs that have occurred in the field of developing new therapies to treat hematological neoplasms. In Oritavancin (LY333328) spite of these discoveries, patients diagnosed with hematological malignancies continue to experience disease relapse and resistance to available treatment options, which suggests that the need to develop novel approaches that can be used alone or in combination with current therapeutic modalities to eradicate hematological neoplasms remains critical. Numerous studies have concluded that the type I insulin-like growth factor receptor (IGF-IR) and its primary ligand IGF-I play significant roles in the establishment and progression of tumors, primarily by inhibiting apoptosis and inducing cellular transformation [7C10]. IGF-IR is also thought to aid malignant cells in acquiring anchorage-independent growth, giving the cells the ability to survive detachment and facilitate migratory processes for metastatic dissemination [11]. To date, there are several potentially effective IGF-IR inhibitors that have been tested in preclinical studies as well as in clinical trials enrolling patients harboring aggressive forms of solid cancers and hematological malignancies. Importantly, these IGF-IR inhibitors are well tolerated with minimal toxic effects [12]. The effects of IGF-IR have been Icam2 studied to a great extent in solid tumors, including those of the breast, prostate, lung, ovary, skin, and soft tissues [13C17]. In contrast, less studies have been performed to thoroughly examine the function of IGF-IR in hematological neoplasms [18C24]. In this review, we discuss the current understanding of the role of IGF-IR signaling in cancer including hematological neoplasms. We also address the emergence of IGF-IR as a potential therapeutic target in the treatment of these aggressive diseases. THE IGF SIGNALING SYSTEM Overview The IGF signaling system plays significant roles in both embryonic and postnatal development as well as having important functions in normal adult physiology. The IGF system includes four receptors: insulin receptor (IR), IGF-IR, IGF-IIR, and the hybrid receptors consisting of one-half IR and one-half IGF-IR (Physique ?(Figure1).1). These receptors interact with three main ligands: insulin, IGF-I, and IGF-II. IR, IGF-IR, and IGF-IIR have the strongest binding affinity for their respective ligands, whereas the binding of insulin to IGF-IR and IGF-I to IR is at least 100-fold less [25]. IGF-I and IGF-II signaling is usually mediated through IGF-IR; but IGF-I has at least 3-fold higher binding affinity than does IGF-II [25]. The Oritavancin (LY333328) IGF system also includes regulatory proteins, known as IGF binding proteins (IGFBPs) that regulate IGF signaling. Although up to 10 proteins have been described in the literature as IGFBPs, only IGFBP-1 thorough IGFBP-6 are considered true IGFBPs based on their conserved protein structure and high binding affinity for IGF-I and IGF-II [26]. Open in a separate window Physique 1 Overview of the IGF systemThe IGF system consists of four receptors: IR, IGF-IR, IGF-IIR, and hybrid receptors. IR is usually expressed as two isoforms – IR-A and IR-B. IR-A has oncogenic potential, expressed predominantly in fetal tissues, and its expression declines during adulthood. IR-B is the physiologically expressed isoform in Oritavancin (LY333328) adult tissues. The IR-A or IR-B receptor makes one half of the hybrid receptors along with one half of the IGF-IR. The IGF system receptors interact mainly with three ligands: insulin, IGF-I, and IGF-II. Excluding IGF-IIR, these receptors possess Oritavancin (LY333328) tyrosine kinase activity. At the other hand, IGF-IIR (also known as mannose-6-phosphate [M6P] receptor) binds and removes circulating IGF-II to keep its free form at very low levels. The physique depicts IGF system ligands in order of.