ANDROGEN-DEPENDENT PROSTATIC TUMORS - BIOSYNTHESIS AND POSSIBLE ACTIONS OF LHRH

Testosterone (T) is the major exogenous stimulus for the growth of pro static carcinoma. It is believed that the proliferative action of T ma y be mediated by locally expressed growth modulatory factors. Recent e vidence from our laboratory suggests that a LHRH (or a LHRH-like) loop might be expressed in human prostatic tumor cells. To verify this hyp othesis, we have studied whether a mRNA for LHRH is expressed in the h uman androgen-responsive prostatic cancer cell line LNCaP, using the r everse transcription-polymerase chain reaction technique in the presen ce of a pair of specific oligonucleotide primers. A cDNA band of the e xpected size was obtained from LNCaP cells; this band hybridized with a P-32-labeled LHRH oligonucleotide probe and its sequence showed a co mplete match with the reported sequence of the human placental LHRH cD NA. These observations indicate that the mRNA coding for LHRH is expre ssed in LNCaP cells and suggest that a LHRH (or a LHRH-like) peptide m ight be produced by these cells. To clarify the possible action of thi s peptide, LNCaP cells were grown in a steroid-free medium and treated with a LHRH antagonist. The treatment resulted in a significant incre ase of tumor cell growth. These data clearly indicate that the LHRH sy stem expressed in LNCaP cells plays an inhibitory role on cell prolife ration, and that this system seems to be regulated in a negative way b y steroids. An EGF/TGF alpha autocrine stimulatory loop (peptides, rec eptors, intracellular signals) is also functional in these cells. Trea tment of LNCaP cells grown in serum-free conditions (i.e. in the absen ce of exogenous growth factors) with a monoclonal antibody against the EGF receptor, or with immunoneutralizing antibodies against EGF or TG F alpha, resulted in a significant decrease of cell proliferation. T p ositively regulates this EGF/TGF alpha system by increasing the concen tration of EGF biding sites. The present data indicate that an inhibit ory LHRH (or LHRH-like) system is expressed in LNCaP cells and partici pates in the local mechanisms regulating tumor cell proliferation toge ther with a EGF/TGF alpha stimulatory loop. Both systems appear to be modulated by T.