Fibroblasts in liver cancer: functions and therapeutic translation

Abstract

Accumulation of fibroblasts in the premalignant or malignant liver is a characteristic feature of liver cancer, but has not been therapeutically leveraged despite evidence for pathophysiologically relevant roles in tumour growth. Hepatocellular carcinoma is a largely non-desmoplastic tumour, in which fibroblasts accumulate predominantly in the pre-neoplastic fibrotic liver and regulate the risk for hepatocellular carcinoma development through a balance of tumour-suppressive and tumour-promoting mediators. By contrast, cholangiocarcinoma is desmoplastic, with cancer-associated fibroblasts contributing to tumour growth. Accordingly, restoring the balance from tumour-promoting to tumour-suppressive fibroblasts and mediators might represent a strategy for hepatocellular carcinoma prevention, whereas in cholangiocarcinoma, fibroblasts and their mediators could be leveraged for tumour treatment. Importantly, fibroblast mediators regulating hepatocellular carcinoma development might exert opposite effects on cholangiocarcinoma growth. This Review translates the improved understanding of tumour-specific, location-specific, and stage-specific roles of fibroblasts and their mediators in liver cancer into novel and rational therapeutic concepts.

Figure 1:. Spatial and temporal differences in fibroblast accumulation and interactions in hepatocellular carcinoma and cholangiocarcinoma

In hepatocellular carcinoma, fibroblasts accumulate in the premalignant environment of the liver, where they interact with hepatocytes but also immune and endothelial cells to regulate the development of hepatocellular carcinoma. In hepatocellular carcinoma tumour lesions, fibroblasts are less abundant than in the surrounding liver but might also exert biological functions. In intrahepatic cholangiocarcinoma, fibroblasts accumulate in the tumour microenvironment, where they interact with tumour cells but also immune and endothelial cells to promote intrahepatic cholangiocarcinoma progression. Both hepatocellular carcinoma and cholangiocarcinoma are often surrounded by cancer-associated fibroblasts and a fibrotic capsule.

Figure 2:. Dual role of fibroblasts and their mediators in chronic liver injury and hepatocarcinogenesis

(A) In early disease stages, cytokine and growth factor-expressing HSCs predominate. Cytokine and growth factor-expressing HSCs-produced HGF predominantly protects from hepatocyte death, which leads to reduced inflammation and fibrosis. Together, this protects the liver from hepatocellular carcinoma development. (B) In advanced disease stages, myofibroblastic HSCs dominate. Via production of type I collagen, they increase stiffness, TAZ signalling in hepatocytes, and promote hepatocyte proliferation, which increases the risk for hepatocellular carcinoma development. In addition, HSCs and HSCs secreted mediators might also contribute to immune cell exclusion and inhibit antitumour immunity and increase angiogenesis (via VEGF secretion), which both also increase hepatocellular carcinoma risk in the liver. HSC=hepatic stellate cells.

Figure 3:. Key fibroblast mediators involved in cholangiocarcinoma growth

(A) Cholangiocarcinoma contains diverse CAF subpopulations including vascular CAF, inflammatory CAF, and myofibroblastic CAF. (B) Vascular CAF promote tumour growth via IL-6 secretion. (C) Inflammatory CAF promote cholangiocarcinoma growth through direct interactions with tumour cells via HGF secretion, which activates tumour cell-expressed MET. (D) Myofibroblastic CAF promote tumour growth via hyaluronic acid secretion. Myofibroblastic CAF-secreted type I collagen does not appear to promote cholangiocarcinoma growth but might have parallel tumour-suppressive functions (eg, physical tumour restraint) and tumour-promoting functions (eg, stiffness and mechanosensitive pathway activation or immune physical and functional exclusion). CAF=cancer-associated fibroblast.

Figure 4:. Targeting fibroblasts and their mediators for hepatocellular carcinoma as single therapy or in combination with targeting of other cellular compartments

(A) Hepatocellular carcinoma prevention strategies include HGF mimetics, decreasing hepatocellular carcinoma risk through decreased hepatocyte death, and a subsequent reduction of inflammation and fibrosis; inhibition of type I collagen production (eg, via small interfering RNA) to decrease liver stiffness, hepatocyte TAZ, and hepatocyte proliferation; or killing of activated HSC (eg, via HSC-targeted liposome HSP47 small interfering RNA), which in addition to decreased stiffness, TAZ, and proliferation might also decrease angiogenesis or improve immunosurveillance. Inhibition or killing of senescent HSCs or fibroblasts (via senolytics or CAR T cells) might achieve similar effects as killing activated HSC and reduce fibroblast and HSCs senescence-associated phenotype. (B) Inhibition of type I collagen production or killing of activated HSCs or cancer-associated fibroblast might synergise with immune checkpoint inhibitors and VEGF inhibition for hepatocellular carcinoma therapy by increasing hepatic or tumour immune cell recruitment and activation, and possibly angiogenesis. Furthermore, DDR1 inhibitors might decrease tumour cell proliferation. HSC=hepatic stellate cells.

Figure 5:. Targeting fibroblasts and their mediators for cholangiocarcinoma therapy

(A) Killing of activated hepatic stellate cells (eg, with navitoclax) might synergise with immune checkpoint inhibitors by increasing immune cell recruitment and activation or with chemotherapy (cisplatin plus gemcitabine) by increasing tumour cell sensitivity to cell death and reducing tumour cell proliferation. (B) Inhibition of HGF or MET via specific inhibitors might synergise with chemotherapy by increasing tumour cell sensitivity to cell death and reducing tumour cell proliferation. It is also conceivable that inhibition of hyaluronic acid production (eg, via inhibition or silencing of HAS2) or its receptors or neutralisation of IL-6 (eg, via tocilizumab) might synergise with chemotherapy via synergistic effects on tumour cell proliferation or through increased sensitivity of tumour cells to cell death. CAF=cancer-associated fibroblast.