Blockade of the insulin‐like growth‐factor‐I receptor inhibits growth of human colorectal cancer cells: Evidence of a functional IGF‐II‐mediated autocrine loop

Abstract

Insulin-like growth factors (IGFs) are potent proliferation stimulators for numerous tumor cells and often function as autocrine growth factors. We have previously shown that exogenous IGF-I and IGF-II enhance proliferation of colorectal carcinoma cells. The biological signal of both factors is transmitted through the IGF-I receptor (IGF-I-R). This receptor was expressed in 12/12 colorectal carcinoma cell lines tested. alpha IR3, a neutralizing monoclonal antibody (MAb) directed against the human IGF-I-R, inhibited proliferation in 7/12 lines (Caco-2, HT-29, LS411N, LS513, LS1034, WiDr and SW620), as reflected by a reduction of MTT conversion (19 to 42%), a decrease in cell number (39 to 72%) and an increase in doubling time (up to 2-fold). In addition, in 4 cell lines (Caco-2, LS513, LS1034, WiDr) alpha IR3 suppressed colony formation in methylcellulose (40 to 84%). Excess of exogenous IGF completely neutralized alpha IR3-mediated inhibitory effects. Northern blot analysis revealed abundant expression of 2 IGF-II transcripts of 5.0 and 4.3 kb in LS1034 cells. In addition, we observed that growth inhibition by alpha IR3 was correlated with a more differentiated phenotype. Our results suggest that growth of many colorectal carcinoma cell lines is regulated by autocrine IGF-II-mediated stimulation of the IGF-I-R.

Oncogene-induced up-regulation of Caco-2 cell proliferation involves IGF-II gene activation through a Protein kinase C-mediated pathway

“…In contrast, in the presence of the anti-IGF-II or aIR3 antibodies but not of isotypic IgG, the number of Caco-2-MT and Caco-2-T cells was closely similar to that of Caco-2-H cells indicating that both antibodies were much more ecient in inhibiting the proliferation of the oncogene-transfected cells (54% inhibition) than the proliferation of control Caco-2-H cells (28% inhibition). This ®nding shows that an IGF-II autocrine loop is involved in the control of Caco-2 cell proliferation, in accordance with the results reported for parental Caco-2 cells (Lahm et al, 1994;Zarrilli et al, 1994). More important, this ®nding indicates that increased autocrine IGF-II production in Caco-2-MT and Caco-2T cells mediates the stimulation of their proliferation and therefore suggests increased endogenous activation of the IGF1Rs in these cell lines.…”

“…Overexpression of IGF-II has been found in 30 ± 40% of colorectal tumors (Tricoli et al, 1986;Lambert et al, 1990), indicating that autrocrine production of IGF-II may also play a role in the deregulation of the proliferation of colon cancer cells. IGF-II is the major IGF secreted by Caco-2 cells (Hoe¯ich et al, 1994;Zarrilli et al, 1994;Park et al, 1996) and evidence was provided that an autocrine IGF-II/IGF1R loop is involved in the control of the proliferation of this cell line (Lahm et al, 1994;Zarrilli et al, 1994Zarrilli et al, , 1996.…”

Cell-cell contact and specific cytokines inhibit apoptosis of colonic epithelial cells: growth factors protect against c-myc-independent apoptosis

“…This may be because HT29 produces IGF-II and signals through the IGF-I receptor (Lahm et al, 1994). Such cell lines may therefore have evolved an autonomous survival pathway.…”

“…IGF-I protects human erythroid colony-forming cells and human IL-3-dependent haemopoietic cells from apoptosis (Rodrigues Tarduchy et al, 1992) and both IFG-I and IGF-II are potent survival factors for oligodendrocytes (Barres et al, 1992). The presence of IGF-I and IGF-II receptors has been reported on normal adult human colonic epithelium (Rouyer-Fessard et al, 1990;Pillion et al, 1993) and both IGF-I and IGF-II are growth stimulatory for many human carcinomas, including colon (Lahm et al, 1994). These observations suggest that the IGFs may promote cell growth or survival in colonic epithelium under physiological conditions.…”

Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas

“…IGF-mediated growth responsiveness is found in most GI cancer cells (15,18,19,22). Aberrant activation of IGF-IR by paracrine and autocrine loops has been reported (22,42), and the expression of IGF-IR/IGF-II may be useful for the prediction of recurrence and poor prognosis in esophageal squamous cell carcinoma (18). Here, we used a new IGF-IR-specific TKI, NPV-AEW541, for the accurate dissection of the responsible signaling pathways.…”