Insuline-Like Growth Factor 1 Is over Expressed in Multiple Myeloma Plasma Cells and Regulates the Expression of the Insuline-Like Growth Factor 1 Receptor.
Authors: Terragna C. , Renzulli M. , Testoni N. , Grafone T. , Tosi P. , Zamagni E. , Cellini C. , Ottaviani E. , Colarossi S. , Iacobucci I. , Poerio A. , Martinelli G. , Baccarani M. , Cavo M. 
Published: October 2019

Abstract
Insulin-like growth factors 1 (IGF1) plays an important role in regulating cell proliferation, differentiation, apoptosis, and transformation. IGF1 acts by binding the type 1 IGF receptor (IGF-1R), thus activating its tyrosine kinase activity. Recent studies have shown that IGF1 is an important survival and growth factor in multiple myeloma (MM).
In this study we evaluated the expression of IGF1 and IGF1-R in a series of 49 newly diagnosed MM patients (pts) primarily treated with thalidomide and dexamethasone. The aim of the study was to correlate the expression of these genes with presenting features of MM pts and to evaluate their relationship with response to therapy.
We isolated the CD138+ cell fraction from bone marrow (BM) samples; IGF1 and IGF1-R expression was evaluated by Real-time RT PCR in both CD138+ and CD138- cells, considering a pool of donors as calibrator (expression value=1). We found that neoplastic CD138+ and CD138- cells expressed widely high levels of IGF1 (median 145.01 and 3.16, range 0.13–1089.92 and 0.02–103.25, respectively), and low levels of IGF1-R (median 0.76 and 2.27, range 0.04–9.38 and 0.21–13.55, respectively). As expected, expression data for both genes, in both cell populations resulted very scattered; in fact no differences could be highlighted in the expression of IGF1 and IGF1-R genes, with respect neither to presenting clinical features, nor to the presence of two of the most frequent MM chromosomal alterations (t(4;14) and del(13)). According to response to induction therapy, pts were divided in two subgroups, including 35 responsive and 14 non responsive pts, respectively. Again, overall no relationship was pointed out between the expression of IGF1 and IGF1-R and response to therapy.
IGF1 is known to regulate IGF1-R at transcriptional level, down-regulating its expression; this mechanism may be autocrine or paracrine. We thus hypothesized that the unexpectedly low IGF1-R expression levels might be the consequence of a negative-feedback regulation mechanism, induced by an IGF1autocrine effect. Nevertheless, we were not able to highlight a significant inverse correlation between the expression values of IGF and IGF1-R in any of the cell fraction analyzed. On the contrary, among responsive pts, a highly significant inverse correlation was highlighted between IGF1 expressed by the CD138+ and IGF1-R expressed by the CD138− cells (p= 0.001), thus suggesting a possible paracrine effect of IGF1 produced by plasma cells exerted on CD138− cells; interestingly, the same effect could not be highlighted in pts non responding to induction therapy. In conclusion, our preliminary data confirmed the possible involvement of IGF1/IGF1R pathway in MM pathogenesis; we suggested the existence of a paracrine effect of IGF1 produced by CD138+ cells, thus emphasizing the importance of the dialog between plasma cells and microenvironment in MM. Moreover, as this mechanism seemed to act only in responding pts, the ability to efficiently regulate IGF1-R expression may have an important prognostic value. The study of post transduction modifications of the IGF1-R will thus be needed, in order to get more insight into the relationship between the IGF and IGF1-R expressions and the receptor activation.