The Liver Pre-Metastatic Niche in Pancreatic Cancer: A Potential Opportunity for Intervention

SIMPLE SUMMARY: Patients with pancreatic cancer have a very poor chance of long-term survival. This is usually due to advanced disease at the time of diagnosis, which commonly includes occult or clinically obvious liver metastases. Emerging evidence suggests that organs that develop metastases exhibit microscopic changes that favor metastatic growth, collectively known as “pre-metastatic niches”. Such pre-metastatic niches result from various signals originating from the primary pancreatic tumor that reprogram immune and other cells in the liver and other organs, thus enabling the growth of cancer cells once they spread. In this review, we summarize the latest discoveries regarding the liver pre-metastatic niche in pancreatic cancer. We are optimistic that intensified future research will help to reveal powerful diagnostic markers and targetable therapeutic pathways, which will ultimately benefit patients. ABSTRACT: Cancer-related mortality is primarily a consequence of metastatic dissemination and associated complications. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and tends to metastasize early, especially in the liver. Emerging evidence suggests that organs that develop metastases exhibit microscopic changes that favor metastatic growth, collectively known as “pre-metastatic niches”. By definition, a pre-metastatic niche is chronologically established before overt metastatic outgrowth, and its generation involves the release of tumor-derived secreted factors that modulate cells intrinsic to the recipient organ, as well as recruitment of additional cells from tertiary sites, such as bone marrow—all orchestrated by the primary tumor. The pre-metastatic niche is characterized by tumor-promoting inflammation with tumor-supportive and immune-suppressive features, remodeling of the extracellular matrix, angiogenic modulation and metabolic alterations that support growth of disseminated tumor cells. In this paper, we review the current state of knowledge of the hepatic pre-metastatic niche in PDAC and attempt to create a framework to guide future diagnostic and therapeutic studies.