Predicting metastatic progression of prostate cancer after first-line therapy

The spreading of prostate cancer cells from the prostate to distant sites in the body (“metastasis”) is a critical factor in why prostate cancers lead to patients’ deaths, … but we still don’t really know what triggers prostate cancer cells (or any other cancer cells for that matter) to metastasize.

Back in 2002 a Frenchman called Jean-Paul Thiery proposed the idea that cancer cells metastasized because they took advantage of a process called “epithelial-to-mesenchymal transition” or EMT. (However, Thiery certainly wasn’t the first to notice a relationship between EMT and cancer metastasis — e.g., one by Birchmeier and Birchmeier in 1995, so the originality of Thiery’s hypothesis is open to some question.)

EMT is a perfectly normal process in developing embryos. In such embryos cells are transformed from epithelial cells (which are normally fixed in a particular part of the organism) into mesenchymal cells (which can migrate to new locations and evolve into new types of tissue and organs). This is how babies develop from the initial clump of dividing cells into an early fetus and then into a fully formed neonate that is ready to be born (complete with  a head, arms, legs, a heart, a brain, etc.).

What Thiery suggested is that, just as EMT can be switched “on” and “off” in embryos, it can also be switched “on” and “off” in cancer cells. If this is the case, then, for example, prostate cancer cells could detach themselves from their point of origin when EMT is turned “on,” and travel through the bloodstream or other channels to start the growth of tumors in bone or elsewhere in the body (“metastasis”). The initial growth of a new micrometastatic tumor would be associated with the turning “off” of EMT among the cells in that new tumor.

To date there have been no real clinical data to substantiate Thiery’s suggestion (although it does carry a good deal of credibility). However, a recently published paper by Behnsawy et al. appears to add credibility to Thiery’s hypothesis.

Behnsawy et al. looked at the patterns of expression of markers of EMT in men with localized prostate cancer and correlated their findings to the clinical outcomes of these men post-treatment. Specifically, the authors looked at data related to a total of 13 different possible markers of EMT (along with more conventional prognostic markers) from 197 consecutive patients with localized prostate cancer, all of whom were treated by radical prostatectomy. They found the following:

  • Expression levels of 4/13 markers for EMT (E-cadherin, Snail, Twist and vimentin) were closely associated with conventional indicators of prostate cancer progression.
  • Based on univariate analysis
    • The same four markers for EMT were significant predictors for biochemical recurrence.
    • Conventional markers of biochemical recurrence included serum PSA level, Gleason score, seminal vesicle invasion, surgical margin status, and tumor volume.
  • Based on multivariate analysis
    • Expression levels of two of the EMT markers (Twist and vimentin) were independently related to biochemical recurrence.
    • Two of the conventional markers (seminal vesicle invasion and surgical margin status) were independently related to biochemical recurrence.
  • There were significant differences in biochemical recurrence-free survival based on the levels of these four independent risk factors.
  • Biochemical recurrence occurred in
    • 4/90 patients (4.4 percent) who were negative for all four risk factors
    • 21/83 patients (25.3 percent) who were positive for one or two risk factors
    • 19/24 patients (79.2 percent) who were positive for three or four risk factors

The authors conclude that measurement of expression levels of potential EMT markers, particularly Twist and vimentin, in post-surgical specimens would contribute to the accurate prediction of the biochemical outcome in patients with localized prostate cancer following radical prostatectomy (in combination with conventional prognostic factors).

This finding, that expression levels of Twist and vimentin are associated with risk for progressive disease, does seem to suggest the possibility that Thiery’s hypothesis about how cancer metastasis occurs has clinical validity (at least in prostate cancer) … but more work will be needed to validate this hypothesis.

3 Responses

  1. Any idea regarding how one is tested for “Twist and vimentin?”

  2. These are highly specialized tests only available in a research setting at the present time (as far as I am aware). The tests can only be carried out on actual prostate cancer tissues from biopsy or prostate pathology specimens

  3. I did check to see if Dr. Bonkhoff offered tests for these. He doesn’t, but I hope he’ll consider it in the future, as these seem even more predictive than the many tests he currently offers.

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