Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissuetype plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Prostate carcinoma is the most commonly diagnosed cancer in men and the second leading cause of death from malignancy in men in the United States (1). If diagnosed after the carcinoma metastazises, prostatic cancer is a fatal disease for which there is no cure (2). Prostate cancer preferentially metastazises to bone where insulin-like growth factors (IGFs) are two of the most abundant growth factors (3). Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR), which could faciliate the development of bone metastases because IGFs are required for cell growth.The IGF-IR has been shown to play a central role in the mechanism of transformation (4). Human prostate cancer cells have been shown to express binding sites for insulin-like growth factor I (IGF-I) (5). Receptor studies have demonstrated the presence of specific binding sites for IGF-I on rat prostate adenocarcinoma cells (PA-III) (6). These cells were obtained from a spontaneously occurring tumor in an aged Lobund-Wistar (L-W) rat (7). The Pollard system of transplantable prostate tumors has been demonstrated to be an extremely useful model for the evaluation of antimetastatic and cytotoxic agents for the treatment of androgen-insensitive prostatic cancer (8,9). Moreover, a recent study strongly supports the validity of the Pollard model of spontaneous prostate cancer in L-W rats (10). Therefore, we have applied our antisense strategy using an IGF-IR construct to study the effect of blocking the IGF-IR on tumorgenesis of transfected PA-III cells in vivo.We have reported that treatment of rat glioblastoma (11) and mouse teratocarcinoma (12) with our antisense constructs to IGF-I resulted in complete regression of tumors in syngeneic animals. Furthermore, an identical antitumorigenic effect has been described for C6 glioblastoma cells that were treated with a similar antisense RNA strategy that targeted the IGF-IR (13). In this study, we demonstrate that the L-W rat prostate cancer cells, PA-III, express the IGF-IR; however, we could not de...
SUMMARY The concentrations of angiotensin converting enzyme (ACE) activity, norepinephrine, and serotonin were measured in microdissected regions of the dog's brainstem and spinal cord. In addition, we determined the in vitro metabolism of 125 I-angiotensin I (Ang I) hi hompgenates of the same brain pnnch regions. High ACE-specific activity was found hi the monoamine-containing regions of the brainstem and in the intermediolateral column of the spinal cord. In brainstem homogenates '"I-Ang I was metabolized to angiotensin II (Ang- [l-8]) and the N-terminal heptapeptide Ang-(l-7). In the presence of MK 422 (50 fiM), Ang-(l-7) was still generated, while the production of Ang-(l-8) was inhibited. This study revealed the presence of high ACE activity in monoamine regions of dog brainstem and spinal cord, and showed that the metabolite Ang-(l-7) is the major product generated from Ang I in the presence and absence of ACE inhibition. (Ang H) in the central nervous system is limited by our lack of knowledge of the functional neurochemistry of the brain reninangiotensin system (RAS) in regions that may produce the peptide for actions on neuronal circuits engaged in autonomic function.12 Because catecholamine neuronal groups of the dorsal and ventral brainstem and the spinal cord have a major role in blood pressure regulation and the evolution of some forms of experimental hypertension, 3 we determined the distribution of the angiotensin converting enzyme (ACE) in these areas in the dog. We studied also the proteolytic hydrolysis of angiotensin I (Ang I) in brain punch homogenates obtained from these regions to evaluate the biochemical pathways that account for the generation and metabolism of angiotensins in the brain.
Insulin-like growth factor-II (IGF-II) expression has been implicated as a major determinant of fetal size during murine pregnancy. It remains unclear whether expression in the fetus, the placenta, or both is the overriding factor controlling growth. To gain further understanding of the placental contribution, we mapped IGF-II expression in the fetal vascular and trophoblastic portions of the late murine placenta (day 9.5-18.5). We found that, as in the fetus itself, vasculogenic mesenchyme, in this case derived from the allantois, was the strongest expressor of IGF-II. Trophoblast, on the other hand, while expressing somewhat less IGF-II, showed a dynamic pattern of IGF-II expression, which reflected its continuing differentiation during late pregnancy. Initially (days 9.5 and 12.5), the spongiotrophoblast, which is homologous to the cytotrophoblast columns and shell in early human pregnancy, strongly expressed IGF-II. Later, expression in the spongiotrophoblast was down-regulated as a new population, the so-called glycogen cells, emerged within the spongiotrophoblast (day 12.5-15.5) and went on to invade the mesometrial decidua. Glycogen cells, which are homologous to human intermediate trophoblast, strongly expressed IGF-II. Trophoblast lining the area of maternal-fetal exchange, the labyrinth, on the other hand, maintained a constitutive lower level of IGF-II expression throughout late pregnancy.
The type I insulin-like growth factor receptor (IGF-IR) plays an important role in the growth and transformation of breast cancer cells. In this study, we investigated the effects of treatment with an antisense IGF-IR construct on cells from the highly metastatic estrogen receptor-negative human breast cancer cell line MDA-MB-435s. The cells carrying the antisense IGF-IR had a markedly reduced expression of IGF-IR, had a significant decrease in cell proliferation, and lost the ability to form colonies in soft agar. There was a delay in tumor formation and a dramatic reduction in tumor size when cells carrying the antisense IGF-IR were injected into either nude or severe combined immunodeficient (scid) beige mice. We have also provided data that show that the scid beige mouse is a more suitable model for studying metastasis of the MDA-MB-435s cells. All of the scid beige mice injected with cells carrying the control construct had metastasis to the lungs, whereas lungs from the nude mice had no apparent metastatic sites after 11 weeks. When cells carrying antisense IGF-IR were injected subcutaneously in scid beige mice, the animals had a significant increase in survival compared with mice injected with cells carrying the control construct. Taken together, these results indicate that the IGF-IR can play a critical role in the progression of breast cancer. Our studies provide a basis for the development of future treatment strategies targeting the IGF-IR in metastatic breast cancer. Cancer Gene Therapy (2000) 7, 384 -395
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