Customizing the Targeting of IGF-1 Receptor

Renato Baserga

Disclosures

Future Oncol. 2009;5(1):43-50. 

In This Article

Colon Cancer & the IGF-IR

The IGF-IR is expressed in both normal colonic mucosa, colon cancer cells and most colon cancer cell lines, including commonly used ones such as HCT116, DLD-1 and CoLo-205.[35,36] There are reports of a role of IGF-I in colon cancer in humans.[35,37] Other supporting evidence for a role of the IGF-IR in colon cancer includes: the observation that IRS-1 deficiency promotes apoptosis in intestinal crypt stem cells,[38] an association between certain IRS polymorphisms and colon cancer,[39] and the modest but significant increase in colon cancer incidence in patients with acromegaly.[40] Although IGF-2 may be the most important ligand in activating the IGF-IR in colon cells (normal and abnormal), it should be remembered (for the purpose of this review) that the IGF-IR is usually targeted with antibodies that inhibit the binding of both IGF-1 and IGF-2 to the IGF-IR. Despite these observations, the accepted wisdom is that other genetic alterations and other growth factors overshadow the role of the IGF-IR in colon cancer.

A totally different situation may exist with colon cancer metastases to the liver. Liver metastases are the main cause of mortality in patients with colorectal cancer.[41] In pathology textbooks (for instance[42]) it is stated that 75% of distant colon cancer metastases are located in the liver (lymph-node metastases are not considered distant). And thereby hangs a tale. The liver produces large amounts of IGF-1; in mice the liver is responsible for 75% of IGF-1 plasma levels.[43] Although colon cancer cells metastasize to the liver because of the vagaries of blood circulation (the portal vein that drains the colon goes directly to the liver), once they are there they find themselves awash in IGF-1 (incidentally, hepatocytes do not express IGF-IRs, otherwise our liver would undergo limitless growth). Regardless of whether they also use other growth factors, colon cancer cells in liver find themselves in an environment favorable to the activation of the IGF-IR, and xenotransplants in mice have confirmed that high levels of IGF-1 favor liver metastases.[44] It is not necessary for the number of receptors to be higher than normal. The colon cancer cells will respond to IGF-1 with growth, and pathologists are well aware that colon cancer metastases in liver are often very, very large. Sometimes they are so large that they are removed surgically by partial hepatectomy. This is another feature that renders this model attractive. Treatment of patients after surgical removal of the primary tumor with antibodies to the IGF-IR to prevent metastases is of course preferable. However, because liver metastases often appear with a long delay, it would probably take several years before one can obtain statistically significant results. On the contrary, clinical experience is that, after partial hepatectomy to remove a metastatic colon cancer nodule, recurrences are common within 1 year. A pilot study on patients that have undergone partial hepatectomy for a single, large colon cancer metastasis can provide a quick answer on the efficacy of targeting the IGF-IR to prevent recurrences. Liver metastases from colon cancer therefore constitute, for several reasons, an excellent model to test the therapeutic effects of antibodies to the IGF-IR. Cancer cells expressing the IGF-IR find themselves in an environment awash with IGF-1, while most normal cells (hepatocytes) are insensitive to IGF-IR targeting because they do not express the receptor. In addition, quick preliminary answers can be obtained.

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