Liver Microenvironment Response to Prostate Cancer Metastasis and Hormonal Therapy

Abstract

Prostate cancer-associated deaths arise from disease progression and metastasis. Metastasis to the liver is associated with the worst clinical outcomes for prostate cancer patients, and these metastatic tumors can be particularly resistant to the currently widely used chemotherapy and hormonal therapies, such as anti-androgens which block androgen synthesis or directly target the androgen receptor. The incidence of liver metastases is reportedly increasing, with a potential correlation with use of anti-androgen therapies. A key player in prostate cancer progression and therapeutic response is the microenvironment of the tumor(s). This is a dynamic and adaptive collection of cells and proteins, which impart signals and stimuli that can alter biological processes within prostate cancer cells. Investigation in the prostate primary site has demonstrated that cells of the microenvironment are also responsive to hormones and hormonal therapies. In this review, we collate information about what happens when cancer moves to the liver: the types of prostate cancer cells that metastasize there, the response of resident mesenchymal cells of the liver, and how the interactions between the cancer cells and the microenvironment may be altered by hormonal therapy.

Keywords: ECM; androgen; hormones; liver; metastasis; microenvironment; niche; prostate cancer.

Figure 1

(A) Liver Lobule Cellular Microenvironment. The liver is comprised of hepatic lobules, which are the microscopic hexagonal subunits of the liver. These consist of a central collecting vein, hepatocyte lined sinusoids leading to hepatic triads, a collection of three ducts; hepatic artery, portal vein, and bile duct. Between the endothelial cells and either hepatocytes or cholangiocytes/bile ducts, is the space of Disse, a region where mesenchymal cells reside, such as stellate cells, dendritic cells/immune cells, and fibroblasts. (B) Metastatic colonization of the liver. Escaping from the primary site, cancer cells invade the circulatory system, through which they navigate to the liver. Once extravasated from hepatic blood vessels and in the liver, cancer cells can undergo cell death or they can remain dormant. From dormancy, cancer cell proliferation can be activated, allow for the formation of micro-metastases, which with continued proliferation become macroscopic metastatic lesions. There is an associated change in the resident cells, with damage to the hepatocytes, increase in ECM due to activation of stellate cells and recruitment of fibroblasts. There is also a potential influx of immune cells.

Figure 2

Characteristics of prostate cancer cells in the liver. A summary of data from Stand Up to Cancer (SU2C) database showing the cellular characteristics of prostate cancer cells that have metastasized to the bone (n = 160), lymph node (n = 167), liver (n = 64), and lung (n = 7). (A) The per-centage of metastatic tumors with pathologist defined neuroendocrine features. Green = metastases with neuroendocrine features, red = no neuroendocrine features, and grey = no characterization available. (B) Analysis of (i) neuroendocrine prostate cancer (NEPC) gene scores and (ii) androgen receptor (AR) activity gene scores in different metastatic sites. (C) Comparison of NEPC (horizontal) and AR (vertical) gene scores in (i) different metastatic sites, and (ii) the liver alone. Analyzed using publicly available data [61].

Figure 3

AR expression in the cells of the liver. Single cell RNA-seq analysis of human liver from two different studies. (A) Liver autopsy samples [118] of 47,001 cells in total from 16 patients. (i) UMAP graph of single cells collected from different patients’ livers. Each sample is colored by which patient they come from, and surrounded by a dotted line indicating which cell types compose each group. (ii) Analysis of AR expression in each single cell, with expression scaled from grey (no expression) to increasing shades of red (increasing levels of AR expression). (B) The Human Liver Cell Atlas Study (GSE192742 [119]), comprised of 4647 cells from human liver. (i) UMAP graph showing the cell-types present in this sample. (ii) Analysis of AR expression in each single cell, with expression scaled from grey (no expression) and deepening shades of blue (increasing levels of AR expression). (iii) Violin plots of AR expression in a sub-set of the cell-types detected in the study.