This antiangiogenic effect may therefore have provided an additional inhibitory mechanism for tumor cells that initially escaped the direct growth inhibitory effects of circulating sIGFIR. Taken together, this suggests that in mice with MSC-derived following website circulating sIGFIR, the bioavailability of IGF-I in the immediate tumor microenvironment was reduced, mimicking the autocrine effects of tumor cell-produced sIGFIR.32 Of note also is our observation that serum insulin and glucose levels in the treated mice were not measurably different than those in the control group, suggesting that nonspecific effects on glucose metabolism in these mice did not play a role in the observed reduction in liver metastasis. We also observed that the antimetastatic effect of the soluble receptor did not decline but rather increased with time (up to 14 days) following MSC implantation.

This suggests that in addition to the direct effects on tumor cell growth, the sustained presence of sIGFIR:IGF-I complexes may also have impacted other, host-dependent factors that normally contribute to the formation of hepatic metastases such as the stromal and inflammatory reactions. Previously we have shown that tumor cells invading the liver initiate a host inflammatory response that promotes tumor cell arrest, intravasation, and metastasis.39,40,41 The IGF axis plays a role in host inflammation and immunity and can modulate cytokine signaling via several mechanisms including JAK/STAT activation.8,42,43 Changes in IGF-I bioavailability could therefore potentially have indirect effects on liver metastases by altering the host inflammatory response to invading tumor cells.

We have shown here that the IGF-IR decoy can prevent the growth of experimental metastases from three different carcinoma cell types. This is consistent with other reports including our own, that have identified IGF-I as a critical factor for liver metastasis8,10,19,35 and suggests that liver metastasizing malignancies may be particularly susceptible to therapeutic modalities that target the IGF axis, possibly due to the high IGF-I content in the liver.6,8,44 The present results identify the soluble IGF-IR as an effective and specific antimetastatic agent and provide a rationale for its further development for clinical use. Materials and Methods Cells. The origin, metastatic phenotype, and culture conditions of H-59��a subline of the Lewis lung carcinoma��were previously described.45 Murine MC-38 colon adenocarcinoma cells46 and human colorectal carcinoma KM12SM Entinostat cells (a kind gift from I.J. Fidler, M.D. Anderson Cancer Institute, Houston, TX) were maintained as described elsewhere.46,47 Mouse bone marrow stromal cells were phenotyped and characterized as has been described in detail previously.