Zetter Research Laboratory | Growth Inhibitors

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.

Purifying and identifying the factor was no easy task, since the inhibitor was a small molecule that contained no protein, lipid or carbohydrate.The job fell to postdoctoral fellow Roy Smith, who eventually identified it as spermine
(NH₂-CH₂-CH₂-CH₂-NH-(CH₂)₄-NH-CH₂-CH₂-CH₂-NH₂). Spermine is 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).

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).

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.