Common Therapy for Prostate Cancer May Promote Metastasis

Reading time: 6 – 10 minutes

A study published in the journal Cancer Research last month suggests that the principle treatment for advanced prostate cancer may actually encourage prostate cancer cells to metastasize [1]. Researchers at The Johns Hopkins University School of Medicine focused on a gene called Nestin, which encodes an intermediate filament protein. Intermediate filaments are cytoskeletal or scaffolding structures found in cells that, in addition to maintaining cell shape, control a variety of cellular processes including proliferation, migration and survival [2]. Nestin gene expression also distinguishes stem cells from differentiated cells and has been shown to be activated in pediatric brain tumors and rhabdomyosarcomas (cancers that develop from skeletal muscle), central nervous system tumors and gastrointestinal stromal tumors [3-6].

The Prostate and cancer

The prostate is a small, walnut-sized gland that is located beneath the bladder and wrapped around the urethra in men. The urethra is a tube that carries urine from the bladder and semen from the epididymis. A male sex gland, the prostate secretes components of prostatic fluid, which forms part of the semen that carries sperm.

The prostate can be affected by a number of problems, including:

  1. Prostatitis (inflammation of the prostate)
  2. Benign Prostatic Hyperplasa (BPH, an enlarged prostate)
  3. Prostate cancer

Prostate cancer is the most common male neoplasia (meaning abnormal proliferation of cells in a tissue or organ) and is the leading cause of cancer death in American men [7]. It is a heterogeneous disease (meaning that the disease consists of a wide spectrum of presentations with variable response to treatment) ranging from asymptomatic to a rapidly fatal systemic malignancy, and progresses from pre-cancerous lesions, termed prostatic intraepithelial neoplasia (PIN), to invasive adenocarcinoma and ultimately to metastatic disease [8-10].

Androgen is the generic term for a group of steroid hormones, including testosterone, that principally influence the growth and development of the male reproductive system. Androgens affect prostatic epithelial cell differentiation and proliferation. The mainstay of treatment for advanced prostate cancer is androgen deprivation therapy, i.e. surgical or medical castration (meaning the use of surgery or drugs to suppress androgen production). However, despite high initial response rates to androgen deprivation, virtually all men progress to androgen-insensitive or androgen-independent prostate cancer. Thus, while early detection and treatment are generally associated with favorable clinical outcomes, there are presently no curative interventions for patients with advanced disease.

Nestin expression is linked to androgen withdrawal and affects cell migration

In cell lines derived from metastatic prostate cancer, Johns Hopkins researchers found that Nestin gene expression was elevated only in androgen-independent cells. They then examined Nestin gene expression in prostate cancer samples from 254 patients that encompassed the entire clinical spectrum of the disease, from untreated localized tumors to lethal metastatic cases. Increased levels of Nestin gene expression were found exclusively in lethal cases following androgen deprivation therapy. nestinNo detectable Nestin was found in prostate cancers that had not been subjected to the therapy. In an androgen-independent cell line derived from metastatic prostate cancer, loss of Nestin expression had no effect on cell viability or growth rate but was shown to greatly reduce cell motility. In a mouse model of human prostate cancer, compared to control tumors, transplanted prostate cancer cells with reduced Nestin expression produced one fourth the number of metastatic deposits and the deposits were dramatically reduced in size. The study thus identifies a specific role for Nestin in cell motility and a novel pathway for prostate cancer metastasis.

In the same issue of Cancer Research, another study in a genetically engineered mouse model of human prostate cancer demonstrated that prolonged exposure of the mice to reduced levels of androgen accelerated prostate tumor development compared to mice exposed to physiologically normal levels of androgen [11]. The mice displayed a molecular profile similar to that of mice with androgen-independent prostate tumors. The finding is significant since the mouse model is based on the loss-of-function of genes known to be relevant for human prostate cancer and is consistent with the conclusions of the first study described above.

Taken together, these results suggest that androgen deprivation therapy encourages prostate cancer cells to accelerate tumor development, making them more likely to spread throughout the body. While these results are too preliminary to alter current clinical practice, the findings warrant further study. Although the effects of androgen deprivation therapy are temporary, it is an effective treatment for slowing prostate tumor growth and can boost the effect of neoadjuvant therapy (e.g. radiation therapy used to shrink a tumor prior to surgical removal).

References

  1. Kleeberger et al. Roles for the Stem Cell-Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis. Cancer Res. 2007 Oct 1;67(19):9199-206.
    View abstract
  2. Coulombe and Wong. Cytoplasmic intermediate filaments revealed as dynamic and multipurpose scaffolds. Nat Cell Biol. 2004 Aug;6(8):699-706.
    View abstract
  3. Almqvist et al. Immunohistochemical detection of nestin in pediatric brain tumors. J Histochem Cytochem. 2002 Feb;50(2):147-58.
    View abstract
  4. Kobayashi et al. Pediatric rhabdomyosarcomas express the intermediate filament nestin. Pediatr Res. 1998 Mar;43(3):386-92.
    View abstract
  5. Dahlstrand et al. Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res. 1992 Oct 1;52(19):5334-41.
    View abstract
  6. Tsujimura et al. Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal. Am J Pathol. 2001 Mar;158(3):817-23.
    View abstract
  7. Cancer Facts & Figures 2007. American Cancer Society. Atlanta, Ga. 2007.
  8. DeMarzo et al. Pathological and molecular aspects of prostate cancer. Lancet. 2003 Mar 15;361(9361):955-64.
    View abstract
  9. Isaacs et al. Focus on prostate cancer. Cancer Cell. 2002 Aug;2(2):113-6.
    View abstract
  10. Nelson and Montgomery. Unconventional therapy for prostate cancer: good, bad or questionable? Nat Rev Cancer. 2003 Nov;3(11):845-58.
    View abstract
  11. Banach-Petrosky et al. Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice. Cancer Res. 2007 Oct 1;67(19):9089-96.
    View abstract
About the Author

Walter Jessen is a senior writer for Highlight HEALTH Media.

Comments

  1. A couple of points here: Nestin isn’t a definitive stem cell marker, but merely a marker, along with Oct-4, that is often but not always found on stem/progenitor cell types.

    Although drawing the conclusions you’re getting to is coming a little close to making a causation out of a correlation, and other possibilities involving Nestin and androgens being co-regulated are possible, I think the conclusions do make some sense. In general, if you make it harder but not impossible for a somewhat heterogeneous group of cells to proliferate, the more aggressive ones will eventually dominate, right? The analogous situation that comes to my mind is hypoxia and HIF-1 stimulating angiogenesis.

  2. Hi Mr. Gunn – you are entirely correct. Things are rarely, if ever, black and white in biology. Nestin is expressed predominantly in stem cells of the central nervous system.

    Indeed, the conclusion that androgen deprivation therapy encourages prostate cancer cells to accelerate tumor development may be correlative. However, strong correlation often warrants further investigation to determine causation. That’s why I indicated that more research needed to be done. Nevertheless, the results of the final experiment in the study in mouse xenografts (transplanted prostate cancer cells expressing Nestin) are far from correlative and clearly demonstrate that Nestin expression is sufficient to increase metastasis.

    I mentioned the second study (engineered mouse model) to show that an unrelated investigation reached a similar conclusion i.e. prolonged exposure to low levels of androgen can promote, rather than prevent, prostate carcinogenesis. In that study, all the mice with normal levels of testosterone (n=15) and all of the mice in the mock group (n=6) displayed low- and high-grade PIN but not cancer. In comparison, over 70% of mice with low levels of testosterone displayed high-grade PIN with invasive carcinoma. Thus, low levels of testosterone are sufficient to promote an accelerated phenotype.

    You raise a valid point regarding the possibility of Nestin being regulated by androgen. I should have indicated that many studies have been performed to identify androgen-regulated genes (ARGs) over the last decade and Nestin has never been identified:

    Xu et al. Quantitative expression profile of androgen-regulated genes in prostate cancer cells and identification of prostate-specific genes. Int J Cancer. 2001 May 1;92(3):322-8.
    View abstract

    DePrimo et al. Transcriptional programs activated by exposure of human prostate cancer cells to androgen. Genome Biol. 2002 Jun 14;3(7):RESEARCH0032. Epub 2002 Jun 14.
    View abstract

    Nelson et al. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11890-5. Epub 2002 Aug 16.
    View abstract

    Segawa et al. Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene. 2002 Dec 12;21(57):8749-58.
    View abstract

    Velasco et al. Identification and validation of novel androgen-regulated genes in prostate cancer. Endocrinology. 2004 Aug;145(8):3913-24. Epub 2004 May 6.
    View abstract

    … if you make it harder but not impossible for a somewhat heterogeneous group of cells to proliferate, the more aggressive ones will eventually dominate …

    Absolutely. The authors of the first study speculate that Nestin expression may provide a selective advantage and the authors of the second study reach a similar conclusion – low levels of testosterone may provide a selective advantage for the outgrowth of androgen-independent prostate cancer cells.

  3. David Berman says:

    Great analysis Walter. This paper has received a lot of attention but this is one of the most cogent summaries. Mr. Gunn has some great points too. We’ll stay busy in the lab.

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  1. […] Walter, the genius behind the fantastic Highlight Health, blogs about recent papers in Cancer Research that presented some alarming news about one common treatment for prostate cancer: We may be shooting ourselves in the foot. (Or the crotch?) It appears that androgen deprivation […]