Why is the liver the most common site of metastatic disease? Part of the reason may be that circulating tumor cells are trapped by the liver, which filters the blood coming from the digestive tract before it reaches the rest of the body. That is not the whole story, however. Metastasis to the liver depends on the formation of a "pro-metastatic niche," which creates the conditions that support the spread of tumor cells to the liver. Until now, little has been known about the mechanisms behind the formation of the pro-metastatic niche, the "soil" in which metastatic cancer seeds and grows. Researchers at the Abramson Cancer Center of the University of Pennsylvania have found the answer: hepatocytes, the liver's main functional cells, coordinate fibrosis—the formation of excess fibrous connective tissue—and the accumulation of myeloid cells, increasing the liver's susceptibility to metastatic seeding and outgrowth.
"The seed-and-soil hypothesis is well recognized, but our research now shows that hepatocytes are the major orchestrators of this process," stated Gregory L. Beatty, MD, PhD, Assistant Professor of Hematology-Oncology at the University of Pennsylvania's Perelman School of Medicine and senior author of the study, which has now been published in Nature.
The researchers found that during the early stages of pancreatic tumor formation in mice, hepatocytes demonstrate activation of signal transducer and activator of transcription 3 (STAT3) signaling, in addition to increased production of serum amyloid A1 and A2, which are collectively referred to as SAA. Patients with pancreatic and colorectal cancers that have metastasized to the liver also have SAA overexpression; in addition, many patients with locally advanced and metastatic disease have increases in circulating SAA.
"The liver is an important sensor in the body," commented Jae W. Lee, an MD/PhD candidate in Dr. Beatty's laboratory and lead author of the study. "We show that hepatocytes sense inflammation and respond in a structured way that cancer uses to help it spread."
In addition to identifying this source of metastasis, the investigators have found a potential solution to the problem. The activation of STAT3 in hepatocytes and the SAA production that follows rely on the release of interleukin 6 (IL-6) into the bloodstream by non-cancerous cells. Through genetic ablation or through blocking the components of the IL-6–STAT3–SAA pathway, the researchers were able to prevent the establishment of a pro-metastatic niche, thereby inhibiting liver metastasis.
Targeting the IL-6–STAT3–SAA pathway creates a new set of therapeutic targets that could potentially help prevent cancer's spread to the liver, which, as the researchers note, is "a major cause of cancer mortality."
For More Information
Lee JW, Stone ML, Porrett PM, et al (2019). Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature. [Epub ahead of print] DOI:10.1038/s41586-019-1004-y
Image courtesy of the National Cancer Institute