Prostate Cancer: An Origin Story

Photo credit: Louis Reed

Photo credit: Louis Reed

The cellular origin of prostate cancer, which has remained a mystery to the scientific community, lost some of its enigmatic charisma this year, as a scientific group led by Dr. Jung Wook Park at UCLA released a study that shed some light on the intricacies of prostate cancer development and progression. Park and his colleagues aimed to resolve a decades-long debate by identifying the cell of origin of prostate cancer, and considering many different cell types make up the prostate, this was no easy task.

Identifying these cells could help scientists develop more targeted, aggressive treatments for prostate cancer and hopefully save countless lives in the medical field.

Image credit: Cancer Research UK

Image credit: Cancer Research UK

Prostate cancer is the most common cancer in the world among men and the sixth leading cause of death, affecting the prostate, a gland found solely in the male reproductive system. This type of cancer can be highly aggressive, often spreading to bones and lymph nodes, and is of significant concern because it shows few symptoms in its initial stages, making it extremely difficult to diagnose before it becomes destructive.

Like all cancers, prostate cancer is just a form of uncontrolled cell growth; if a prostate cell is exposed to a condition that stops it from regulating its growth, it may begin to divide uncontrollably, leading to tumors and the damaging conditions associated with cancers. 

Among prostate cancer researchers, the ongoing debate on which prostate cells actually initiate cancerous growth has been narrowed down to two cell types: basal epithelial cells and luminal cells. Interestingly, cancerous cells in prostate tumors appear to have a “luminal phenotype,” or display characteristics similar to luminal cells, but scientists have never been able to transform human luminal cells into effective cancer cells, only basal cells.

This strange phenomenon has led scientists in the field to believe that basal cells are the only type of prostate cells that can initiate tumor growth and the progression of prostate cancer.

To test this theory, Park and the authors designed a study in which they used a lentivirus, a type of virus that we can pack genetic information of our choosing into and then infect specific cells, to transfer two specific types of oncogenes, or cancer-causing genes, into both basal cells and luminal cells. Through a process called transduction, the virus was able to inject these cancer-causing genes of interest into luminal and basal cells, where these genes incorporated themselves into the cell’s genetic material, and could initiate cancer progression.

Example of cell characterization based on fluorescent protein markers. Credit: Olympus Lifescience

Example of cell characterization based on fluorescent protein markers. Credit: Olympus Lifescience

The researchers performed this part of the experiment to determine if both types of cells could be converted to cancer-causing agents, and were able to verify that both luminal and basal cells could become cancerous through the presence of a fluorescent marker that the virus also transferred to the cell.

If the cells fluoresced, or glowed a certain color after being infected with the virus, it meant that the genetic material (the oncogenes and the fluorescent marker) were successfully incorporated into the cell’s genetic material. These oncogenes made these cells cancerous.

Next, the authors allowed the cancerous basal and luminal cells to develop into organoid cultures, or 3D structures of cells that simulate the organ of interest (in this case, a prostate). Keep in mind this is happening outside the body, and is not causing further harm to the patient; this presents a powerful method for testing potential treatments on patient-specific prostate cancers without harming the patient, and this study represents one of the first successful uses of organoid cultures to study tumor growth.

Park and his colleagues also grew organoid cultures from normal basal and luminal cells (prostate cells that had not been made cancerous through the transduction of oncogenes), and after two weeks, noticed that organoids with oncogenes (the cancerous type) had grown significantly larger than organoids lacking oncogenes. This makes sense, considering we expect cancerous cells to grow faster than non-cancerous cells; these cells are not able to regulate their growth!

Diagram of the process by which the authors created organoid cultures from basal and luminal cells infected with a vector containing cancerous oncogenes. Credit: Park et al. 2016

Diagram of the process by which the authors created organoid cultures from basal and luminal cells infected with a vector containing cancerous oncogenes. Credit: Park et al. 2016

What Park and his colleagues noticed, however, is that cancerous basal cells behaved differently than cancerous luminal cells. This was revolutionary: prostate cancer was expected to develop similarly regardless of the original cell type. Park’s data showed that oncogene-transduced basal cells grew much faster than the oncogene-transduced luminal cells, leading to larger tumors and more unorganized structure; both characteristics of more aggressive, malignant cancers. A scale used to determine the aggressiveness of prostate cancer (the Gleason scale) placed the basal cell-derived tumors at a whopping 9 out of 10, with 10 being the worst, and placed luminal cell-derived tumors at only 6 out of 10.

This data suggests that basal cell-derived tumors are of significantly more concern than tumors that originate from luminal cells, and may require more of a focus in clinical studies to treat prostate cancer.

Overall, the data gathered by Park and his colleagues reveals a critical piece of knowledge in the field of prostate cancer research; to understand the disease as a whole (and later develop treatments for it), we must first understand its origins. This study proved that transduction can be used to transform luminal cells into cancer cells, which was previously thought to be unfeasible, and that basal and luminal cells that become cancerous act differently, with luminal cell-derived tumors behaving significantly less aggressively than basal derived tumors.

Ultimately, this research confirms that different cells of origin lead to different cancer phenotypes, and this conclusion can be applied to all different types of cancer we see today. Park and the other authors provide a necessary framework upon which the study of prostate cancer development can be built upon, and a promising step towards successful treatments in the future.   

-Jason


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