American College of Surgeons 90th Annual Clinical Congress

NEW ORLEANS—Surgeons from the John Wayne Cancer Institute, Santa Monica, CA, have identified what may be a key mechanism by which cancer metastasizes to the liver, according to a study presented at the 2004 annual Clinical Congress of the American College of Surgeons (ACS). Results from the study show that the chemokine receptor CXCR4 genes--typically quiescent or downregulated in normal cells, is in liver metastases from patients with colorectal cancer and melanoma. CXCR4, usually found on immune cells, was shown not only to be present on cancer cells but also to be functional. When cancer cells bearing the CXCR4 receptor were stimulated by the protein (CXCL12) that binds to them, there was a significant increase in cell migrational activity.

"We know that other factors for cancer metastasis exist, but we think CXCR4 may play a major role in liver metastasis. By our initial analysis, we found that this was the most common chemokine receptor in patients with colorectal cancer and melanoma liver metastasis," Joseph Kim, MD, a fellow in surgical oncology at John Wayne Cancer Institute, said. Chemokine receptors typically play a critical role in orchestrating immune cells to specific sites during immunologic response; it appears that cancer cells use this same mechanism.

Further research could lead to the development of drugs that target the CXCR4 receptor to treat cancers that metastasize to the liver. Cancer cells that metastasize to the liver may bear the CXCR4 chemokine receptor, so they can be an alternative target for therapy. "Industry is currently producing methods to specifically target cancer cells by targeting the CXCR4," Dr. Kim said.

Because most patients with cancer can die from distant organ metastasis, there has been a focus to determine why or how cancer spreads to specific organ targets. One theory, known as the homing or signaling mechanism, relies on the activities of receptors on the surface of malignant cells. Dr. Kim's research on the CXCR4 receptor provides some support for that theory. "CXCR4 is a specific receptor for one particular protein (CXCL12), which is highly produced by the liver. It supports the signaling or homing hypothesis in that the cells that have this receptor will aim for or migrate toward the organ that produces the highest level of the protein, such as the liver," he explained.

Researchers from other institutions have shown that chemokine receptors affect metastasis in cell cultures and animal studies. Dr. Kim and his associates wanted to determine whether the chemokine receptor CXCR4 influenced metastasis in patients with cancer. "Our focus was to find out whether there actually was clinical relevance and similarity of function for chemokine receptors of melanoma and colorectal cancers that metastasize to the liver," Dr. Kim said.

In a previous study, presented at the 2004 meeting of the American Society of Clinical Oncology, Dr. Kim showed that there was significant upregulation of CXCR4 in liver metastases from patients with colorectal cancer. Among patients with stage I or II colorectal cancer in this study, 30 percent who had high CXCR4 expression developed local or distant metastasis. However, none of the patients with low expression of the chemokine receptor showed signs of metastasis after 39 months of follow-up.

In the study reported at the 2004 annual ACS Clinical Congress, Dr. Kim and his associates focused on melanoma as well as colorectal cancer. "We thought if the chemokine receptor aided in colorectal cancer metastasizing to the liver, it might promote metastasis in other cancers. So we looked at colorectal cancer and melanomas to see if the same mechanism for two completely different cancers led to or aided in forming liver metastasis," he explained.

The study used microarray technology, which assesses multiple genes in a single experiment, to screen for the presence of chemokine receptors on the surface of cancer cells in liver metastasis samples from patients with melanoma and colorectal cancer. This analysis revealed that CXCR4 was the most commonly expressed chemokine receptor by both cancers. CXCR4 was expressed in 13 of 16 tumor specimens from patients with melanoma metastasis and all 22 specimens from colorectal patients with liver metastatic disease.

The researchers then assessed how the CXCR4 receptors functioned on cancer cells by treating cancer cells with the protein that binds to the CXCR4 receptor, CXCL12 (stromal cell-derived factor-1, [SCDF-1], and then measuring cellular migrational activity. "Just having a receptor doesn't necessarily mean that it actually does something. So we wanted to establish that the receptors on the cell surfaces were functional. We found that higher numbers of cancer cells responded to the protein than control cells," Dr. Kim said. The rate of response to CXCL12 was greater in melanoma and colorectal cancer cells than in control cells. "This finding shows that the protein leads to a transformation in the cell machinery," he explained.

Dr. Kim and his colleagues are conducting further studies to learn how the CXCR4 chemokine receptor may be altered by environmental factors. He also is trying to determine if the receptor is expressed by other liver metastases. "CXCR4 may play a role in the mechanism of metastasis for not only melanoma and colorectal cancer. It may be important for all cancers that metastasize to the liver," he said.

Also participating in the study were Takuji Mori, MD, PhD; Stella Lam, BS; Lonnissa Nguyen, BS; Donald Morton, MD, FACS; and Anton Bilchik, MD, PhD, FACS. The study was supervised by Dave SB Hoon, PhD.

News from the 2004 Clinical Congress