Professor, carcinogenesis, University of Texas MD Anderson Cancer Center
• Associate professor, carcinogenesis, University of Texas MD Anderson Cancer Center — 2005-2010
• Adjunct associate professor, School of Pharmacy, University of Texas at Austin, — 2005-2010
• PhD, cancer biology, Wayne State University Medical School — 1994
• MS, molecular oncology, Wuhan University School of Medicine — 1989
Researchers from MD Anderson Cancer Center, in collaboration with Mirna Therapeutics, this week published data in Nature Medicine showing that the microRNA miR-34a inhibits prostate cancer stem cells, as well as metastasis, in tumor-bearing animal models of the disease by repressing the adhesion molecule CD44.
The findings, the investigators wrote, support the development of miR-34a as a treatment for prostate cancer.
This week, Gene Silencing News spoke with Tang about the paper.
How about we start with your lab and research focus?
At this moment, our lab's focus is cancer stem cells, especially … in prostate tumors. We have identified a few populations of cells that can initiate prostate cancer at very low numbers [in animal models of the disease.] … And they can do it again and again. Basically, they can re-initiate serially transplantable tumors.
One of the populations of cancer stem cells is harbored in prostate cancer cells that express high levels of a cell surface adhesion molecule called CD44. That's actually one of the populations we screened against in the Nature Medicine paper.
The paper focused on miR-34a. Can you give a little background on it?
We did not really start with miR-34a, actually. We began the project a few years back when [reported on] a very tumorigenic sub-population of prostate cancer cells, which is the CD44-positive population. Around the same time, several other groups also reported other populations of putative prostate cancer progenitor cells.
At that time, microRNAs had already been shown to play critical roles in regulating embryonic stem cells. We thought that perhaps these microRNAs might also be important in regulating cancer stem cells.
We focused on the CD44-positive population, but we also included a few other populations of tumor progenitors … and did a microRNA library screen, which was the part of the collaboration with Mirna Therapeutics.
That screen gave us a few microRNAs that were specifically and reproducibly reduced in all the cancer stem cell populations. One of [them] … miR-34a … was significantly under-expressed in all the CD44-positive prostate cancer cells, [which] was also verified in about 20 primary patient tumors. We immediately felt that this microRNA must be very important.
Two months later, a couple of papers came out … showing that miR-34a is a major p53 target. Everybody knows that is a hardcore tumor-suppressor gene that is mutated in more than 50 percent of [solid] tumors in humans. That was pretty consistent with our initial hypothesis that miR-34a probably has tumor-suppressor functions; that's why it is under-expressed in cancer stem cell populations.
That's how we got to miR-34a. From that moment on, we focused on that microRNA with some straightforward questions in mind [about whether] over-expressed miR-34a in CD44-positive cancer cell populations would inhibit tumor development and metastasis. Vice versa, if we over-express an antagonist of miR-34a in CD44-negative cells, would we see promotion of tumor development and metastasis?
We were lucky that the results turned out, in most of the cases, in support of our hypotheses.
Can you give an overview of the work published in Nature Medicine?
In the paper, we focused on prostate cancer stem cells and basically purified [them] from several prostate cancer xenografts. We identified several microRNAs that are specifically under-expressed in cancer stem cell-enriched populations.
We took that to primary human tumor samples and found that they corroborated the findings from the xenografts. Subsequently, we focused on one of the under-expressed microRNAs, miR-34a.
Because miR-34a was identified as a p53 target, we [examined its] expression in about 12 different cell lines [and found] its expression correlated with p53. Then we carried out over-expression experiments by re-expressing miR-34a in the cancer stem cell populations and in all the cases we observed a very strong inhibition of tumor regeneration and metastasis.
Then we did the opposite experiment by reducing endogenous miR-34a expression in [CD44-negative cells], and we observed enhanced tumor regeneration and metastasis.
Most significantly, in several orthotopic prostate cancer models we allowed the tumors to develop first, and then systemically gave miR-34a to the animals. In five sets of therapeutic experiments, we consistently observed inhibition of tumor development, inhibition of metastasis, and in two sets of experiments we observed extensions of survival of tumor-bearing animals.
To delve a little deeper into the potential mechanisms by which miR-34a might be inhibiting tumor development and metastasis, we carried out extensive in silico analyses and, surprisingly, found that CD44 itself appears to be a very good direct target of miR-34a.
We carried out a variety of functional assays to prove that, indeed, CD44 itself is a very relevant and important target of miR-34a.
This is the first time that there has been genome-wide microRNA expression profiling in prostate cancer stem cells. It is the first time it has been shown that miR-34a is a powerful negative regulator in prostate cancer stem cells … and the first time that CD44 has been identified as a direct target of miR-34a.
What are your thoughts on the therapeutic potential for miR-34a?
In the case of prostate cancer and [other solid tumors,] virtually all of the current therapeutics are targeted at differentiated cells. We have virtually nothing against undifferentiated, stem cell-like cancer cells.
In the case of prostate cancer, all [of the existing therapies] surround [the] androgen receptor. … They basically block androgen signaling, but prostate cancer stem cells will generally not respond well to the current hormone-based therapeutics. They also don't respond well to the common chemotherapeutic drugs, which target rapidly proliferating cells, mainly because cancer stem cells are not actively proliferating.
From this perspective, we have provided proof of principle that certain bioactive molecules, in this case miR-34a, can directly be utilized [as therapy], perhaps in conjunction with the conventional chemotherapeutics.