Hepatic stellate cells: partners in crime for liver metastases?

Abstract

Hepatic stellate cells (HSCs) were recently postulated as a component of the prometastatic liver microenvironment, because they can transdifferentiate into highly proliferative and motile myofibroblasts that are implicated in the desmoplastic reaction and metastatic growth. This review focuses on bidirectional interactions between tumor cells and HSCs in the liver microenvironment and discusses mechanisms whereby tumor-derived factors activate HSCs, and in turn, activated HSCs promote metastatic growth. Bidirectional interactions between tumors and HSCs may function as an "amplification loop" to further enhance metastatic growth in the liver. The activation of HSCs is a complex process regulated by multiple factors such as transforming growth factor-β and platelet-derived growth factor signaling pathways, which may present as therapeutic targets in the prevention and treatment of liver metastases.

Conclusion: HSCs may present a new therapeutic target in the treatment of liver metastases. Targeting HSCs and/or myofibroblasts with transforming growth factor-β or platelet-derived growth factor antagonists in coordination with chemotherapy, radiotherapy, or surgery may prove to be effective at reducing liver metastases and increasing the survival benefit of patients by targeting both tumor cells and the tumor microenvironment.

Figure 1. A schema illustrating bidirectional interactions between tumor and HSC that regulate HSC activation and metastatic growth in the liver

Bidirectional interactions may function as an “amplification loop” to enhance metastatic growth in the liver. Tumor-derived factors such as TGF-β and PDGF promote HSC activation and transdifferentiation into myofibroblasts. In turn, activated HSC promote metastatic growth by multiple mechanisms: (1) production of growth factors and cytokines; (2) regulation of ECM turnover; (3) promotion of tumor angiogenesis; and (4) inhibition of immune cell functions. Tumor cells also modulate their growth by similar mechanisms. In addition to HSC, other potential origins of myofibroblasts in the liver include portal fibroblasts, bone marrow derived fibrocytes, hepatocytes or cholangiocytes.

Figure 2. Tumor cell-activated HSC express α-SMA and contribute to the desmoplastic reaction of liver metastases

Human L3.6 pancreatic cancer cells were implanted into mouse livers by portal vein injection. α-SMA immunofluorescence (green) was performed on cryosections containing micrometastases (upper panels) and macrometastases (lower panels). Cell nuclei were counterstained by ToTo-3 (blue). Note that foci of micrometastases are surrounded by α-SMA positive myofibroblasts and that intrametastatic stroma contains abundant myofibroblasts. M: micrometastase; L: liver. Bars: 100 μM.