Acquisition of paclitaxel resistance is associated with a more aggressive and invasive phenotype in prostate cancer, "Beyond the Abstract," by John J. Kim, Kenneth J. Pienta and Steven M. Mooney

BERKELEY, CA (UroToday.com) - Although thousands of compounds have been synthesized for cancer therapy, cancer has found a way to overcome and surpass the therapeutic capacity of each and every drug. As a result, one of the challenges to the successful treatment of cancer is drug resistance. Paradoxically, cancer cells can evolve to overcome treatments, while normal cells remain the same, making selectivity a major unresolved issue.[1]

In prostate cancer, treatment resistance affects 30 000 patients per year.[2] These patients are normally first treated with androgen deprivation followed by chemotherapy. However, they eventually become insensitive to both therapies and their cancer becomes fatal. In this study, and others, cancer cells incubated for long periods of time in chemotherapy become >100-fold more resistant to the specific drug used.[3, 4] In fact, our previous work indicates that there is a transient resistance gained by temporary incubation of cells in chemotherapy and a permanent transition mediated by long-term incubation of cells in chemotherapy.[5]

Although it is well known that Multi Drug Resistance gene 1 (MDR1) is the cell surface efflux pump that removes toxins such as chemotherapeutics,[6] upregulation of MDR1 is unlikely to be the sole mechanism that cancer cells develop against chemotherapy. Previous data, from several groups, would suggest that it cannot be, since resistance is largely gained to one type of chemotherapy and not to a wide spectrum of drugs with different mechanisms of action.[7] This observation would strongly support the idea of a more complex mechanism than just the MDR1 pump.

Our recent study, published in the Journal of Cellular Biochemistry, demonstrates that chemotherapy causes an epithelial to mesenchymal transition (EMT) which MDR1 is a part of. EMT is a process that transforms cancer cells into an aggressive form that can invade into tissue and form tumors at secondary sites.[8] Interestingly, thus far, only a few prostate cancer cell lines that were derived from sites outside the prostate have been made resistant to chemotherapy.[9] This is somewhat surprising since these cells must have already gone through an EMT to transit through the blood to distant organs such as the bone and brain. In order to rationalize this, we hypothesize that in the body, cells must become more mesenchymal to reach an organ, however to begin the process of proliferation, they must transform back to epithelial cells. The time to differentiate into the epithelial phenotype is the lag phase, or dormancy period.

Based on our study, a strenuous chemotherapy treatment can trigger prostate cancer cells to become more aggressive. This suggests that we need to think carefully about how to use and sequence these agents. Unfortunately, it is difficult to study a perfect drug resistant model using laboratory techniques. In our models, only proliferating cells in culture flasks are studied without the full context of normal cells and biological microenviornment. Future studies need to involve single cell studies of primary and metastatic tumors to truly understand how cells act in vivo and characterize how drugs interact with cells in the individual, as well as holistic levels.

References:

  1. Barrett MT, Lenkiewicz E, Evers L, et al. Clonal evolution and therapeutic resistance in solid tumors. Front Pharmacol 2013;4: 2.
  2. Brawley OW. Trends in prostate cancer in the United States. J Natl Cancer Inst Monogr 2012;2012(45): 152-6.
  3. Kim JJ, Yin B, Christudass CS, et al. Acquisition of paclitaxel resistance is associated with a more aggressive and invasive phenotype in prostate cancer. J Cell Biochem 2012.
  4. David GL, Yegnasubramanian S, Kumar A, et al. MDR1 promoter hypermethylation in MCF-7 human breast cancer cells: changes in chromatin structure induced by treatment with 5-Aza-cytidine. Cancer Biol Ther 2004;3(6): 540-8.
  5. Li Y, Zeng Y, Mooney SM, et al. Resistance to paclitaxel increases the sensitivity to other microenvironmental stresses in prostate cancer cells. J Cell Biochem 2011;112(8): 2125-37.
  6. Enokida H, Shiina H, Igawa M, et al. CpG hypermethylation of MDR1 gene contributes to the pathogenesis and progression of human prostate cancer. Cancer Res 2004;64(17): 5956-62.
  7. Takeda M, Mizokami A, Mamiya K, et al. The establishment of two paclitaxel-resistant prostate cancer cell lines and the mechanisms of paclitaxel resistance with two cell lines. Prostate 2007;67(9): 955-67.
  8. Mooney SM, Rajagopalan K, Williams BH, et al. Creatine kinase brain overexpression protects colorectal cells from various metabolic and non-metabolic stresses. J Cell Biochem 2011;112(4): 1066-75.
  9. Girard FP, Byrne J, Downes M, et al. Detecting soluble clusterin in in-vitro and in-vivo models of prostate cancer. Neoplasma 2010;57(5): 488-93.

 

Written by:
John J. Kim, Kenneth J. Pienta, and Steven M. Mooney* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

*Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Room E7616, Baltimore, MD  USA

Acquisition of paclitaxel resistance is associated with a more aggressive and invasive phenotype in prostate cancer - Abstract

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