How Colorectal Tumors Initiate Metastasis

A team of researchers from Spain and the United States have found a key pathway that is responsible for metastasis initiation of colorectal tumors to the liver-a frequent metastasis site for this tumor type. The researchers-from the Catalan Institution for Research and Advanced Studies (ICREA) in Barcelona, and Memorial Sloan Kettering Cancer Center in New York-demonstrate how colorectal cancer cells establish communication with healthy stromal cells surrounding the tumor cells, ultimately allowing the tumor cells to colonize other sites of the body. The cross-communication between the cancer cells and the stromal cells in other organs provides a survival advantage for the cancerous cells to grow in these distant organs. The research is published in Cancer Cell.

Low magnification micrograph of a mucinous adenocarcinoma of the colon, H&E stain. Source: Nephron, Wikimedia Commons

The study found that the transforming growth factor beta (TGF-β) protein signaling is crucial for the metastatic process in colorectal cancer. “This paper elegantly showed that it is in fact TGF-β signaling in stromal cells that promote liver metastasis by colorectal cancer cells,” said Yibin Kang, PhD, professor of molecular biology at Princeton University, New Jersey. Yang studies the process of metastasis, but was not involved in this published research.

TGF-β is a secreted protein that can affect the activity of surrounding cells and is crucial for cell growth and differentiation, and has been found to be important in the cancer process in many different tumor types. In the current study, colorectal cancer cells secreted the protein which then was able to affect the surrounding stromal cells in the liver.

“We show that metastasis depends on a gene program expressed by the tumor microenvironment upon TGF-β stimulation,” said Alexandre Calon, PhD, ICREA, lead author of the paper. The research, added Calon, demonstrates that normal stromal cells majorly contribute to the metastatic process that depends on a “TGF-β orchestrated crosstalk of [the stromal cells] with the cancer cells.”

A Test for Colorectal Cancer Relapse Risk?

Detection of TGF-β secreted by colorectal cancer cells was a negative prognostic marker that correlated with a high risk of colorectal cancer relapse after treatment. The data suggests that TGF-β signaling from the cancer cells to the stromal cells boosts the efficiency of tumor cell colonization in other organs. Based on these results, researchers may be able to develop a test to predict a colorectal cancer patient’s risk of relapse and metastasis.

Almost half of colorectal cancer patients are either initially diagnosed with advanced, metastasized disease, or they develop metastasis after initial therapy. Identifying risk factors for recurrence and disease progression and the mechanism by which metastasis happens remains a real challenge. This current study suggests that TGF-β signaling within the stromal cells in the tumor’s microenvironment is a potential target for therapy. Potential treatments may be able to target this signaling pathway in the stromal cells or prevent TGF-β secretion by colorectal cancer cells in order to thwart the metastatic process during its initiation.

This research also demonstrates that measuring the TGF-β signaling within the stroma could predict which patients are at high risk for relapse-patients with low TGF-β signaling in their stroma suggests longer disease free-survival compared to those patients with high TGF-β signaling.

About half of the patients had high levels of TGF-β but were free of metastasis at the time of surgery, according to Calon. Of these high TGF-β patients, about half went on to develop metastasis during the 10-year follow-up period. In contrast, the 17% of patients in the study who had low TGF-β levels did not relapse even when they were diagnosed with advanced, stage III colorectal cancer.

The Role of TGF-β Signaling in Cancer

TGF-β signaling in cancer is complicated-it is known to promote metastasis by different mechanisms. Many late-stage cancers produce TGF-β, secreting it into the tumor microenvironment to promote growth and metastasis to other organs. In breast cancer for example, TGF-β signaling promotes bone metastasis by inducing certain genes such as JAGGED1, and lung metastasis by inducing other genes and signaling pathways. “The situation is different in colorectal cancer, which is often defective in TGF-β signaling although the tumor cells [themselves] produce higher amount of TGF-β,” said Kang.

The current research studied 345 different colon cancer patient samples from patients in Barcelona, showing that tumor cells that reach the liver are able to establish communication with the surrounding stromal cells in this tissue including fibroblasts, endothelial cells, and macrophages. The tumor cells secrete TGF-β and the stromal cells respond by producing interleukin 11 (IL-11) that allows the tumor cells to survive in the foreign organ. According to the authors, the TGF-β signaling also blocks apoptosis, or cell death of the tumor cells in this new organ environment.

Eduard Batlle, PhD, Elena Sancho, PhD, and colleagues demonstrated that blocking the TGF-β communication between the colorectal cancer cells and the stroma prevented the initiation of metastasis. Mice that had aggressive colorectal cancer tumors and were given a TGF-β inhibitor did not readily develop metastasis compared to those mice that were not treated with the inhibitor.

“The stromal TGF-β signature has strikingly strong prognostic power for metastasis, giving us a potentially highly effective way to predict patient outcome which will inform treatment decision,” said Kang.

Various strategies to inhibit TGF-β signaling in cancer patients can be explored, including the TGF-β inhibitor used in the current mouse studies, LY2157299. “Although their efficacy is not yet known, our observations predict that pharmacological inhibition of TGF-β signaling may prevent colorectal cancer relapse and metastasis when treating patients at early time point of the process,” said the authors in the paper’s discussion.

The use of recombinant IL-11, shown in this study to encourage metastasis, is currently given to treat the thrombocytopenia that comes with myelosuppressive chemotherapy. “The pro-metastatic effect of IL-11 that we described calls for a reassessment of the use of this cytokine in an adjuvant setting,” said Calon.

The authors are currently working on research to support the ability of TGF-β to predict colorectal cancer relapse “The prediction capacity of TGF-β signaling will be tested in larger scale,” said Calon.

Do other tumor types also depend on a relationship of stromal and cancer cells for metastasis initiation? “It will be very interesting to explore this hypothesis and to understand the pro-metastatic program for other cancers,” said Calon.