Customizing the Targeting of IGF-1 Receptor

Renato Baserga

Disclosures

Future Oncol. 2009;5(1):43-50. 

In This Article

Metastases & the IGF-IR

Metastases are very susceptible to IGF-IR targeting.[46,51,52,53,54] When Long et al.[51] subcutaneously injected wild-type lung cancer cells or the same cells stably expressing an antisense to the IGF-IR (at that time the method of choice for targeting the IGF-IR), local tumor growth was inhibited by only 50%, but metastases to the lungs were inhibited by 90%. Dunn et al.,[46] using a dominant-negative mutant of the IGF-IR in primary xenografts of breast cancer cells, found a 50% decrease in the growth of primary transplants, but complete abrogation of metastases. The rationale for the effectiveness of IGF-IR targeting on metastases is that, at least experimentally, targeting of the IGF-IR is much more dramatic on cells in anchorage independence than on cells in monolayer.[7] A striking example of the difference between growth in monolayer and growth in soft agar in cells with a downregulated IGF-IR is given in Figure 2. In this experiment, melanoma cells were treated with an antisense oligodeoxynucleotide to the IGF-IR.[7] The antisense treatment had little or no effect on the growth of melanoma cells in monolayer, whether in serum or serum plus IGF-1. However, the effect on growth in soft agar (in 10% serum supplemented by IGF-1) was dramatic. Not everybody agrees that anchorage independence actually exists in human tumors. If it does, then the closest approximation to colony formation in soft agar may be small clusters of tumor cells in local recurrences or distant metastases, when the cells have not yet established cell-to-cell interactions and blood vessels. We often wait for metastases or recurrences to appear before we start chemotherapy. In the case of IGF-IR targeting, a possible preventive treatment is indicated (for instance, in the above-mentioned case of colon cancer, treatment with IGF-IR antibodies should be started immediately after surgical removal of the primary tumor).

Figure 2.

Human melanoma cells. The two sets of columns on the left are the number of cells in monolayer plus IGF-1. The columns on the right are number of colonies in soft agar.

The use of melanoma cells in this experiment brings up an unusual biological observation that re-enforces our hypothesis on the growth of colon cancer cells in liver. Uveal melanoma metastasizes most commonly to the liver, where it grows vigorously.[55] There is no explanation for it metastasizing to the liver, as the rules of blood circulation do not connect the eye to the liver. One possible explanation is that uveal melanoma cells duly metastasize to the lungs, where they do not grow because they do not find a welcoming reception there. From the lungs, metastatic cells can be disseminated elsewhere in the body, and it is intriguing that metastatic uveal melanomas express higher levels of IGF-IRs than primary tumors, and that they are sensitive to IGF-IR targeting.[55,56] This model is another one, similar to the Ewing's sarcoma model, that could be highly rewarding in giving us clues to the sensitivity of tumor cells to IGF-IR targeting.

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