Prostate Tumor Origin Dictates Cancer Aggressiveness

The type of cell that gives rise to a prostate tumor may dictate the aggressiveness of that tumor. Research led by Michael Shen and Zhu Wang of Columbia University Medical Center in New York suggests that tumors originating from a certain type of prostate gland cell are more likely to be associated with a poor patient prognosis. The study is a step forward in determining how to identify which prostate cancer patients may need more aggressive treatment.

Using mice, Shen and colleagues showed that two different types of prostate gland cells can be transformed to give rise to two different types of prostate tumors. Each tumor exemplifies a distinct molecular prostate cancer subtype with distinct gene expression. When applied to clinical data, these mouse molecular subtypes were predictive of human patient outcomes. The study is published in Nature Cell Biology.

“A cell of origin is defined as a normal tissue cell that can give rise to a tumor when transformed,” Wang says. “The cell of origin tumor model states that different cells of origin may be a basis for distinct cancer subtypes that can be associated with different patient outcomes.”

The prostate gland consists of three types of epithelial cells—basal, luminal, and the more rare neuroendocrine type. There are also intermediate cells that have both basal and luminal characteristics, as well as stem cells.

In the study, Shen and colleagues first asked whether both basal and luminal cells could generate prostate tumors. They labeled basal and luminal cells that also carried a mutation in the PTEN gene (the most frequent genetic mutation in human prostate cancers) and tracked the ability of these cells to form prostate tumors in mice. Both cell types produced tumors.

The study also found that the basal cells had a unique plasticity. That is, some basal progenitor cells divided to form cells that were luminal-type prostate cells. The result corresponds with previous in vitro studies that found stem cells in prostate basal epithelial tissue. However, the researchers showed that the proportion of basal cells with stem cell properties is lower in mice than was previously thought.

“This result is novel and unexpected and underscores the importance of using a lineage-tracing approach to study physiologically relevant adult stem cells,” Wang says.

To determine whether prostate tumors originating from either basal or luminal prostate cells were molecularly similar, the scientists analyzed both histology and molecular characteristics. Both cell types gave rise to tumors with similar histology, but these tumors were molecularly distinct.

Molecular differences between the two different types of tumors were explored by analyzing the whole-genome expression patterns of both tumor types. Sixty-eight genes were overexpressed in luminal origin tumors. Interestingly, the same genes were also overexpressed in tumor samples from high-risk prostate cancer patients. (These patients had succumbed to their prostate cancer within 12 months of diagnosis.) In contrast, basal cell origin tumors did not overexpress these high-risk genes. The results suggest that luminal cell origin tumors are more aggressive than basal origin tumors.

The signature of 68 genes that were highly expressed in luminal origin tumors was also examined in expression datasets developed by other researchers from multiple tumor biopsies.  Again, this gene signature was highly correlated with poor patient prognosis, and accurately separated primary prostate cancers into high- and low-risk groups.

This research addresses a major question in cancer biology—whether tumorigenesis in different cell types results in distinct tumor phenotypes and influences prognosis and treatment response. For prostate cancer, it now appears that the origin of tumor cell does matter, as tumors arising from luminal cells in the prostate are more aggressive than tumors arising from basal prostate cells.

The study also suggests the existence of molecular prostate cancer subtypes, which were previously elusive. The gene expression signature Wang, Shen, and colleagues identified may lead to a biomarker signature to identify patients with high-risk prostate cancer.

The lab is currently investigating the mechanisms behind the more aggressive characteristics of luminal origin tumors. “The goal is to provide more accurate biomarkers and novel therapeutic targets for blocking cancer progression,” Wang says. The team is collaborating with clinicians to validate and test some of the biomarkers identified in human prostate cancer samples.