Throughout the whole course of the illness, from the early stages to the point of androgen independence, where the tumour no longer responds to hormone restriction treatment, researchers have detailed prostate cancer cell dynamics at a single-cell resolution.
Their research in mice, which was published in the journal eLife, shows that prostate cancer exhibits a proliferation of intermediate cells, which is associated with treatment resistance and worse clinical outcomes in people. These cells are castration-resistant, which explains why prostate tumours can resist hormone-related therapies since they can develop even in the absence of testosterone. The most often diagnosed kind of cancer and the second-leading cause of cancer-related deaths among men in the US is prostate cancer.
The likelihood of developing castration-resistant prostate cancer and the lack of comprehensive understanding of the cellular mechanisms behind the disease’s development are both major contributors to this (CRPC).
The two types of epithelial cells that make up the prostate gland epithelium, a type of biological tissue that forms the surface of glands and organs, are basal cells and highly-differentiated luminal cells (cells which have altered in form). However, it has previously been suggested that the luminal cells can develop into a more stem-like, castration-resistant intermediate.
“It has been suggested that normal luminal cells are able to transition into these progenitor cells under castrate conditions,” says lead author Alexandre Germanos, a PhD candidate in Molecular and Cellular Biology at the University of Washington, US, and a graduate student at the Division of Human Biology, Fred Hutchinson Cancer Center, US. “There is evidence that these cells contribute to the initial development of tumours in the prostate and resistance to treatment in advanced cancers, although this is yet to be confirmed in other models of CRPC.”
Germanos and colleagues created a “map of prostate cellular composition and evolution” over the course of the illness using a mouse model of CRPC in order to better investigate this.
Most individuals with advanced prostate cancer have inactive Pten, a gene that codes for an enzyme that suppresses tumours. The scientists compared the populations of epithelial and non-epithelial cell types in Pten-deficient mice with healthy mice using a method known as single-cell RNA sequencing.
They discovered basal, luminal, and luminal progenitor cells among other epithelial cell types in the prostates of healthy mice. They noticed a proliferation of luminal intermediate cells in the prostates of Pten-deficient animals, which were probably produced from basal cells, luminal progenitor cells, and developed luminal cells. This supports recent research in the area and demonstrates that basal cells can develop into intermediate cells after Pten ablation.
The scientists also noticed that after hormone deprivation, malignant intermediate cells continued to grow, greatly increasing the variety of cells inside a tumour (known as tumour heterogeneity). They showed that preventing protein production can limit this heterogeneity.
The scientists then worked to define the effects of this intermediate cell growth brought on by hormone deprivation. They found that a 5-gene signature is especially concentrated in the intermediate cells. They demonstrated that the signature is linked to treatment resistance and subpar clinical outcomes using two datasets of bulk RNA-sequencing data from prostate cancer patients. A fraction of metastatic human prostate cancer cells—tumors that can spread—also exhibit the signature’s enrichment, but not the originating tumour cells.
These results imply that a 5-gene signature established from prostate cancer animal models may be significant for understanding human illness. The existence of this gene signature may be a helpful prognostic indicator for predicting patient outcomes and treatment resistance. The authors request more research to confirm the function of this signature and intermediate-like cell types in men with prostate cancer.
Additionally, their investigation showed that the prostate of mice lacking Pten is substantially enriched for immune cells that encourage the growth of tumours, resulting in a microenvironment that aids tumours in evading immune system suppression.
Epithelial cells and fibroblasts, a kind of cell that aids in the formation of connective tissue, attract pro-tumorigenic macrophages, a specialised cell type involved in the elimination of dangerous organisms. In order to overcome immunotherapy resistance in prostate cancer, it may be possible to stop the recruitment of tumor-associated macrophages.
“Overall, our work highlights multiple epithelial and immune cell types that are crucial to prostate cancer initiation and progression, and sheds light on the interactions between specific cell populations that contribute to castration-resistance,” concludes senior author Andrew Hsieh, Associate Professor in the Division of Human Biology, Fred Hutchinson Cancer Center, and the Department of Medicine and Genome Sciences (affiliate), University of Washington.”We wanted to provide a broad, searchable resource for cancer researchers and encourage further research in the area. We’ve therefore developed a publicly accessible and interactive website that allows scientists to run cell- and gene-specific queries through all 50,780 cells analysed in our study.”
