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Prostate Cancer is the most common cancer in American males and the second leading cause of cancer deaths in males. Prostate cancers have several distinctive properties. These tumors often grow very slowly in the prostate. In fact, the majority of men with prostate cancer will not have metastases to other organs and will not die of prostate cancer. However, when prostate tumor cells do escape from the prostate, they frequently form metastases in the spine and these metastatic colonies often grow rapidly and are life-threatening. Early prostate cancers rarely have the capacity to metastasize. It often takes years or decades for the tumors to develop a series of mutations that allow the cells to form metastases outside of the prostate. Our research on prostate cancer has the following goals:
Certain tumors tend to metastasize preferentially to particular organs. Prostate cancer is a superb example of this kind of behavior as prostate tumors most commonly metastasize to bone, especially to the vertebrae of the spinal column. Our earliest work on this tumor was designed to ask whether there were factors in bone that could stimulate the growth of prostate cancer cells. Work done by Marcela Chackal-Roy, a graduate student in our lab, showed that bone marrow did indeed contain factors that stimulated the growth of metastatic prostate cancer cells. This work revealed suggested that the reason why prostate cancer metastases grow so rapidly in the spine is because of these bone-derived growth factors. (Stimulation of human prostatic carcinoma cell growth by factors present in human bone marrow. Chackal-Roy M, Niemeyer C, Moore M, Zetter BR J Clin Invest 1989; 84: 43-50)
Gretchen letıs link each reference to a medline site that shows in publication style (as the title and abstract appeared in the journal). Then we will add a figure from each publication. The figure will be visible in this section without any additional clicking but the reader will need to click on the reference to see the abstract.
Marcela then went on to purify one of these growth factors and show that it was transferrin, an iron-binding protein that is known to stimulate the growth of certain cell types. Transferrin is particularly rich in bone marrow where it is used in trannsporting iron to new red blood cells. Thus, a protein particularly abundant in bone marrow has the ability to stimulate the growth of prostate cancer cells that escape the prostate and reach the spine. (Chackal-Rossi M, Zetter BR. Selective stimulation of prostatic carcinoma cell proliferation by trans-ferrin. Proc Natl Acad Sci USA. 1992; 89:6197-6201.)
Stimulation of prostate cancer cells by human bone marrow-derived transferrin (_) compared with stimulation by control serum albumin (o).
If prostate cancer cells grow rapidly in the spine because of the presence of growth factors in bone marrow, then why do the tumor cells tend to grow so slowly in the prostate. A possible explanation was offered by Mark Litwin, a surgical resident at the time who is now on the faculty of urology at UCLA medical school. Mark argued that the prostate might contain naturally occurring inhibitors of prostate cancer growth and he showed that prostate extracts could inhibit the growth of cultured prostate cancer cells. The job of purifying and identifying the factor fell to Roy Smith, a post-doctoral fellow in the lab. The effort was made more difficult when it turned out that the inhibitor was a small molecule that was contained no protein, lipid or carbohydrate. Roy finally identified the inhibitor as spermine a naturally occurring member of the polyamine family that is particularly abundant in the prostate. (Smith RC, Litwin M, Lu Y, Zetter BR. Identification of an endogenous inhibitor of human prostate carcinoma cell growth. Nature Medicine. 1995: 1:1040-1045.
SPERMINE
In a continuation of this work, Chieko Koike, a post-doctoral fellow, demonstrated a potential mechanism for spermine inhibition of prostate cancer cell growth. She showed that a protein called antizyme was induced by spermine in prostate cancer cells that were inhibited by spermine. She also found that some very aggressive, highly metastatic prostate cancer cells become resistant to spermine. In the resistant cells, no antizyme was induced by spermine treatment. These results suggest that the induction of antizyme by spermine treatment is responsible for the growth inhibitory effects of spermine on prostate cancer cells (Koike C, Chau DT, Zetter BR. Sensitivity to polyamine-induced growth arrest correlates with antizyme induction in prostate carcinoma cells. Cancer Res. 1999; 59:6109-6112).
Scan Fig 2A from Cancer Res Paper Caption: Antizyme is induced by spermine-treatment in spermine sensitive AT2.1 cells but not in spermine-resistant AT3.1 cells.
A new model for the regulation of prostate cancer cell growth in prostate and bone.
Our work supports the following theory of prostate cancer growth regulation. A normal function of the prostate is to produce high concentrations of spermine. Initially, most prostate cancer cells have their growth arrested or retarded by the locally high levels of spermine. The mechanism of inhibition involves the induction of antizyme by spermine. This growth arrest causes the early prostate tumors to grow very slowly, often taking decades to reach the diameter of a pea. At some point, however, some of the tumor cells may become resistant to spermine, unable to produce antizyme in response to the local spermine. These cells will be released from growth inhibition and be able to grow more rapidly in the prostate. Tumors comprised of these resistant cells will grow faster and be more likely to escape from the prostate and form metastases in the spine and other distant sites. Those prostate cancer cells that do reach the spine may grow rapidly there because of the presence of transferrin and other growth factors.
One of the most important unsolved problems in prostate cancer today is to find a way predict the eventual outcome of an individualıs prostate cancer at the time he is first diagnosed. Although the PSA test has allowed considerably earlier diagnosis of prostate cancer, a positive PSA only tells that there is prostate cancer present today. It does not predict what will happen to that cancer tomorrow. What is necessary is to find prognostic markers that will tell which tumors will stay confined to the prostate over time and which are at risk for metastasis. In prostate cancer, a marker may be considered predictive if it can distinguish which patients require immediate treatment and which patients can safely be monitored over time without immediate radiation or surgery.
The best diagnostic markers are those that distinguish an early tumor from normal tissue. If such a marker is present in a tumor or in the blood of a patient, then a tumor is likely present. The best predictive markers may be those that arise later in the course of tumor development; those that arise around the time that the tumor is becoming metastatic. The presence of such markers at the time of diagnosis may be sufficient to indicate that a patient is at risk of developing cancer metastases. We have made an effort to find such markers for human prostate cancer.
We have found one marker that appears promising as a predictive marker for prostate cancer. Called thymosin beta 15 or TB15, this molecule regulates the rate of movement of prostate cancer cells. Normal cells and early cancer cells make no TB15. As cells become metastatic, the levels of TB15 begin to rise and the cells become able to move faster (Bao L, Loda, M, Janmey PA, Anand-Apte B, Zetter BR. Thymosin _15: A novel regulator of tumor cell motility upregulated in metastatic prostate cancer. Nature Medicine. 1996; 2:1322-1328). Rapid movement is an important component of metastatic tumor cells (Please see the section of this web site on "cell migration").
Fig. 3 Immunostaining of human prostate carcinoma tissues with an affinity-purified anti-TB15 C-terminal peptide antibody. A. Nonmalignant prostatic epithelia show no TB15 staining (large arrow), occasionally prostatic intraepithelial neoplasia shows weak staining (small arrow). B. Moderately differentiated prostate carcinomas show heterogeneous staining in a single prostate (small arrow, positive; large arrow, negative). C. Poorly differentiated invasive prostate carcinoma cells show strong TB15 staining. D. Single cells invading stroma show intense cytoplasmic staining.
New results in our laboratory show that the presence of TB15 in prostate cancer patients at the time of diagnosis correlates with the later development of recurrent or metastatic prostate cancer 1-11 years following surgery to remove the prostate. Patients who are TB15 positive at the time of diagnosis have a very high probability of having recurrent disease as evidenced by elevated PSA or positive bone scan at some time following surgery. In contrast, patients with no evidence of TB15 in their cancer cells are much less likely to have a tumor recurrence, regardless of the initial grade of the tumor.
We believe that thymosin beta 15 is a prototype for a new class of tumor marker whose presence or absence can be used as an indication of the eventual outcome of the tumor. Such predictors are useful not only in prostate cancer but in breast cancer and other tumors where there are multiple treatment options. We do not believe that any one marker will be perfect in predicting outcomes but rather that panels of such markers will be compiled for each tumor type and used to predict the likely outcome and best treatment protocol for individual patients.
