The Insulin-like Growth Factor System and Colorectal Cancer

Abstract

Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated molecules, they participate in numerous pathophysiological processes, including cancer development. Colorectal cancer (CRC) is a disease with high incidence and mortality rates worldwide, whose etiology usually represents a combination of the environmental and genetic factors. IGFs are most often increased in CRC, enabling excessive autocrine/paracrine stimulation of the cell growth. Overexpression or increased activation/accessibility of IGF receptors is a coinciding step which transmits IGF-related signals. A number of molecules and biochemical mechanisms exert modulatory effects shaping the final outcome of the IGF-stimulated processes, frequently leading to neoplastic transformation in the case of irreparable disbalance. The IGF system and related molecules and pathways which participate in the development of CRC are the focus of this review.

Keywords: colorectal cancer; genetic regulation; insulin-like growth factor system; signaling; therapy.

Figure 1

Global bivariate maps representing the link between human development index (HDI) and colorectal cancer incidence (A) or mortality (B). The boundaries expressed on this map do not imply the expression of any opinion whatsoever concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. Data source: WHO, UNDP [2,6].

Figure 2

Multiple-stage neoplastic transformation of the colon tissue.

Figure 3

Schematic presentation of IGF1R/IR-dependent cell signaling pathways and molecules altered in CRC. Upward and downward red arrows indicate a direction of change. IR—insulin receptor; IGF—insulin-like growth factor; IGF1R—insulin-like growth factor receptor; IGFBP—IGF binding protein; IRS—insulin receptor substrate; PI3K—phosphoinositide 3-kinase; Akt—protein kinase B; GSK3β—glycogen synthase kinase 3-β; Bcl-xL—B-cell lymphoma extra-large; mTOR—mammalian target of rapamycin; Shc—Src homology and collagen adaptor protein; Ras—rat sarcoma virus-related protein; Raf—serine/threonine-specific protein kinase; MEK—mitogen-activated protein kinase; ERK—extracellular signal-regulated kinase.