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Research: Sotiris Malatos, Hendrik Neubert, Andrew T. Kicman, and Ray K. Iles Identification of Placental Transforming Growth Factor-ß and Bikunin Metabolites as Contaminants of Pharmaceutical Human Chorionic Gonadotrophin Preparations by Proteomic Techniques Mol Cell Proteomics 2005; 4: 984-992 [Abstract] [Full text] [PDF]

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TGF{beta} receptor antagonism may explain urinary hCG effects on Kaposi's sarcoma growth

Ray Iles   (13 June 2005)

Human chorionic gonadotropin and Kaposi’s sarcoma

Thierry Simonart   (12 June 2005)

TGF{beta} receptor antagonism may explain urinary hCG effects on Kaposi's sarcoma growth 13 June 2005
Ray Iles, Professor of Biomedical Sciences, Director of Research and Postgraduate Studies School of Health and Social Sciences, Middlesex University, Enfield UK Send letter to journal: Re: TGF{beta} receptor antagonism may explain urinary hCG effects on Kaposi's sarcoma growth ray{at}iles.net Ray Iles	Dr Simonart makes a valid point about the paradoxical actions of hCG on tumor cell growth. For some twenty years I have been studying the ectopic expression of the free beta-subunit of hCG (hCGb) by mucosal epithelial tumors, such as that of the bladder (1). My group and others have shown that it was marker of a highly aggressive malignancy with a propensity to metastasis (2), but also that it enhanced tumor growth by inhibiting apoptosis (3). Reports that hCG induced apoptosis in Kaposis sarcoma, and was being used in Clinical trials, were perplexing (4). However, our in vitro studies enabled us to explain these apparently contradictory findings in a single mechanistic hypothesis, which we published in Clinical Cancer Research (5). Essentially, we presented evidence to propose that free hCGb was acting as an antagonist of the TGFb receptor. TGFb is a bi-functional molecule, which stimulates growth of mesothelium-derived tissues and apoptosis in those cells arising from the epithelia. Normally TGFb would control epithelial cell growth by inducing apoptosis, but by antagonistic blockade of these receptors the death signal can be silenced. However, in mesothelial-derived tissues, such as lymphoid cells, TGFb is a required growth factor and blockade of the TGFb receptor would inhibit growth and even induce apoptosis. Kaposis sarcoma is a mixture of vascular endothelia (probably lymphatic), overgrown with spindle cells. The exact ontogenic origin of the tissues is unknown but Dr Simonart’s work has indicated that the spindle cell component is of mesothelial origin (6). The free hCGb component of any commercial intact hCG preparation could have brought about KS tumor regression via the mechanism proposed. However, the focus has shifted towards a contaminant of the preparations being responsible for the anti Kaposis sarcoma activities reported. Our recent publication has focused purely on the identification of contaminants found in pregnancy urine hCG preparations CG-10 (Sigma), Pregnyl (Organon), and Profasi (Serono). Surprisingly, we found m-pTGF-b, m-bik, and possibly a metabolic product of tumor associated trypsin inhibitor (TATI). It is very likely that the anti-HIV-Kaposis sarcoma activity ascribed to urinary hCG preparations is a result of multi-component effects. Protease inhibitors are an important component of the therapeutic drug cocktails for the effective treatment of HIV-Kaposis sarcoma (7), and hence the presence of bikunin or TATI may be cumulative to any anti-HIV-Kaposis sarcoma activity found in urinary hCG preparations. However, the consistent finding was that of m-pTGF-b within all preparations. TGF-b cysteine knot growth factors activate their receptors by binding as homodimers, recruiting multi-component receptors to an active complex. Since only a monomeric pTGF-b fragment (m-pTGF-b) was detected (particularly in the two commonly used pharmaceutical preparations, Pregnyl and Profasi), it is possible that this metabolite is acting as an antagonist in a potentially more effective manner than that proposed for hCGb. This hypothesis would, in fact, be consistent with Dr Simonart’s findings that first trimester urine potentiates KS cell growth (8). In the first, and beginning of the second, trimester, the trophoblast is at its most invasive, remodeling uterine vessels. Placental TGFb will be at it highest, and is likely to be released into maternal urine. However, this unaltered pregnancy urine is almost certain to contain significant quantities of the bio-active pTGFb dimer, as apposed to the antagonistic metabolite m-TGFb we had detected in the processed clinical grade hCG preparations. Thus the bio-active pTGFb dimer of the first trimester would stimulate mesothelial KS spindle cell growth. I am in full agreement with Dr Simonart; further investigations are urgently required to test this hypothesis. (1) R.K. Iles, R.T.D. Oliver, M. Kitau, C. Walker & T. Chard. (1987) In vitro secretion of human chorionic gonadotrophin by bladder tumour cells. Br.J.Cancer 55, 623 626. (2) R. K. Iles & S A Butler. (1998), Human urothelial carcinomas - a typical disease of the aged: The clinical utility of chorionic gonadotrophin in patient management and future therapy. Experimental Gerontology 33, 379-391. (3) S.A. Butler, M.K. Ikram, S. Mathieu and R.K. Iles. (2000), The increase in carcinoma cell population induced by the free beta subunit of human chorionic gonadotrophin is a result of an anti-apoptotic effect and not cell proliferation. Br J Cancer. 82, 1553-1556 (4) Gill PS, Lunardi-Iskandar Y, Louie S, Tulpule A, Zheng, T, Espina BM, Besnier JM, Hermans P, Levine AM, Bryant JL, Gallo RC. (1996), The effects of preparations of human chorinic gonadotrophin on AIDS-related Kaposi’s sarcoma. NEJM 335, 1261-1269. (5) S.A. Butler, R.K. Iles. (2003), Review - ectopic hCGb secretion by epithelial tumors and hCGb induced apoptosis in kaposi’s sarcoma - is there a connection? Clin. Cancer Res. 9,4666-4673. (6) Simonart T, Degraef C, Heenen M, Hermans P, Van Vooren J-P and Noel J-C. (2002), Expression of the fibroblast/macrophage marker 1B10 by spindle cells in Kaposi's sarcoma lesions and by Kaposi's sarcoma-derived tumor cells. J Cutan Pathol. 29, 72-78 (7) Sgadari, C., Monini, P., Barillari, G., and Ensoli, B. (2003) Use of HIV protease inhibitors to block Kaposi’s sarcoma and tumour growth. Lancet Oncol. 4, 537-547. (8) Simonart T, Hermans P, Delogne-Desnoeck J, Van Vooren JP, Meuris S. (2002), Stimulation of Kaposi's sarcoma cell growth by urine from women in early pregnancy, the current source for clinical-grade human chorionic gonadotrophin preparations. Exp Dermatol. 11, 365-369.
Human chorionic gonadotropin and Kaposi’s sarcoma 12 June 2005
Thierry Simonart, M.D. Department of Dermatology, Erasme University Hospital, B-1070 Brussels, Belgium Send letter to journal: Re: Human chorionic gonadotropin and Kaposi’s sarcoma tsimonar{at}ulb.ac.be Thierry Simonart	Using proteomic mass spectrometry, Malatos and colleagues demonstrated that metabolites of placental transforming growth factor-beta and bikunin may be the contaminating moieties responsible for the reported anti-Kaposi’s sarcoma (KS) activity of some human chorionic gonadotropin (hCG) preparations (1). As outlined by the authors, these findings could provide new perspectives for the treatment of KS. However, it may be regrettable to restrict the effects of hCG preparations to anti-KS effects. Some crude hCG preparations have a paradoxical growth effect on KS cells (2), which may be related to partial co-purification of a mitogen during the industrial extraction process of the drug (3). Consistently, the results of clinical studies using hCG preparations in human KS remain highly contradictory, showing either partial remissions and/or stabilization of the disease in some studies, or absence of effect or even progression in other ones (3,4). Nevertheless, the results reported by Malatos et al further support that investigation of the role of hCG-related factors in cancer is warranted. REFERENCES 1. Malatos, S., Neubert, H., Kicman, A.T., Iles, R.K. (2005) Identification of placental transforming growth factor beta and bikunin metabolites as contaminants of pharmaceutical human chorionic gonadotrophin preparations by proteomic techniques. Mol Cell Proteomics Apr 25; [Epub ahead of print]. 2. Simonart, T., Hermans, P., Van Vooren, J.P., Meuris, S. (1999) Paradoxical pro-Kaposi’s sarcoma activity of preparations of human chorionic gonadotropin. Blood 94, 376-377. 3. Simonart, T., Hermans, P., Delogne-Desnoeck, J., Van Vooren, J.P., Meuris, S. (2002) Stimulation of Kaposi’s sarcoma cell growth by urine from women in early pregnancy, the current source for clinical-grade human chorionic gonadotropin preparations. Exp Dermatol 11, 365-369. 4. Simonart, T., Van Vooren, J.P., Meuris, S. (2002) Treatment of Kaposi’s sarcoma with human chorionic gonadotropin. Dermatology 204, 330- 333.