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Dear Sir,

We read with interest the article by Straughn et al.,“Expression of sperm protein 17 (Sp17) in ovarian cancer”.1 Although this study is a significant contribution to the field of cancer research, the following observations need to be made.

Sperm protein 17 (Sp17) is a highly conserved mammalian protein detected in mouse, monkey, baboon, macaque and human (HSp17) testis and spermatozoa. Using a pair of sequence-specific primers, the presence of HSp17 mRNA has been clearly shown in 17% of patients with multiple myeloma and in the primary tumor cells from 70% of patients with ovarian carcinoma.2, 3, 4 Chiriva-Internati et al.5 have further shown that HSp17 contains functional cytotoxic T-lymphocyte epitopes. These results indicate that HSp17 is a cancer-testis (CT) antigen in multiple myeloma and ovarian carcinoma and suggest its suitability as a target for immunotherapy of these 2 neoplastic diseases.

CT antigens constitute a group of proteins expressed in histologically different types of neoplasia and whose expression in normal tissues is limited to germ cells of the testis, with occasional expression in female reproductive organs.6, 7

Although Sp17 has been frequently reported to be expressed solely in the testis, transcripts have recently been detected in murine somatic tissues by RT-PCR, albeit in much lower amounts when compared to testis.8 Despite Lim et al.4 having failed to detect mRNA encoding HSp17 in human somatic tissues other than the testis, Frayne and Hall9 have clearly detected HSp17 transcripts of the predicted size in a panel of human cDNAs including the brain, heart, kidney, liver, lung, pancreas, placenta and testis.

In clinical materials, the expression of CT antigens has mostly been studied at the level of gene expression by RT-PCR. However the information provided by this approach is limited because of the impossibility of quantifying cancer cells that are positive for CT antigens.7, 10 On the contrary, by means of specific antibodies it is possible to recognize the presence of the antigen within examined tissues, highlighting not only the quantity but also the type of cells immunopositive for that antigen.

By using self-produced mouse anti-HSp17 antibodies, normal human seminiferous tubules were highly positive for HSp17 as well as the flagella of the ejaculated spermatozoa.11 Since the flagella of spermatozoa are similar to cilia, we then investigated whether HSp17 was identifiable in human ciliated epithelia. We detected a strong presence of HSp17 in ciliated epithelia of the respiratory airways and both the male and female reproductive system.12

These data extend recent reports in which a proteomic analysis of human airways cilia revealed the expression of HSp1713 and in which a RT-PCR analysis from a panel of human cDNAs showed HSp17 transcripts in all human tissues examined, including lung and other organs that contain different amounts of ciliated cells.9 Since cilia have been adapted as versatile tools for many biological processes, such as left-right axis pattern formation, cerebrospinal fluid flow, sensory reception, mucociliary clearance and renal physiology,14 it is reasonable to expect that HSp17 may be involved in many complex functions other than sperm-egg interaction as originally suggested.15 Interestingly, we have recently ascertained that melanophages of cutaneous melanocytic lesions express HSp17 and that the presence of this protein is strictly correlated with the amount of melanin deposits.16 The wide functional range of HSp17 should further be investigated in the light of this new information.

In conclusion, all these additional findings seriously question the usefulness of HSp17 in immunotherapy protocols and suggest the need for a) a reevaluation of the role of HSp17 as CT-antigen because of its wide expression in somatic tissues; b) a clearer distinction between laboratory in vitro results (target antigens discovery and in vitro validation) and their application in vivo (in vivo validation) (actually, these results render the use of HSp17 for clinical purposes very premature) and c) a more complete experimental approach that forcefully includes both morphological and molecular analysis, which is imperative to attach the label of “useful target” to any antigen that could be used for therapeutic purposes.

Although the article of Straughn et al.1 discusses important points in the field of ovarian cancer, the information herein presented are necessary for the advancement of knowledge in a currently and widely debated field of investigation.

Yours sincerely,

REFERENCES

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  • 1
    Straughn JM, Jr, Shaw DR, Guerrero A, Bhoola SM, Racelis A, Wang Z, Chiriva-Internati M, Grizzle WE, Alvarez RD, Lim SH, Strong TV. Expression of sperm protein 17 (Sp17) in ovarian cancer. Int J Cancer 2004; 108: 80511.
  • 2
    Chiriva-Internati M, Wang Z, Salati E, Bumm K, Barlogie B, Lim SH. Sperm protein 17 (Sp17) is a suitable target for immunotherapy of multiple myeloma. Blood 2002; 100: 9615.
  • 3
    Chiriva-Internati M, Wang Z, Salati E, Timmins P, Lim SH. Tumor vaccine for ovarian carcinoma targeting sperm protein 17. Cancer 2002; 94: 244753.
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    Lim SH, Wang Z, Chiriva-Internati M, Xue Y. Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Blood 2001; 97: 150810.
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    Chiriva-Internati M, Wang Z, Pochopien, Salati E, Lim SH. Identification of a sperm protein 17 CTL epitope restricted by HLA-A1. Int J Cancer 2003; 107: 8635.
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    Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 2002; 188: 2232.
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    Juretic A, Spagnoli GC, Schultz-Thater E, Sarcevic B. Cancer/testis tumour-associated antigens: immunohistochemical detection with monoclonal antibodies. Lancet Oncol 2003; 4: 1049.
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    Wen Y, Richardson RT, Widgren EE, O'Rand MG. Characterization of Sp17: a ubiquitous three domain protein that binds heparin. Biochem J 2001; 357: 2531.
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    Frayne J, Hall L. A re-evaluation of sperm protein 17 (Sp17) indicates a regulatory role in an A-kinase anchoring protein complex, rather than a unique role in sperm-zona pellucida binding. Reproduction 2002; 124: 76774.
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    Chiriva-Internati M, Grizzi F, Franceschini B, Hermonat PL, Bright RK, Bumm K, Dioguardi N, Kast WM. Is sperm protein 17 a useful target for tumor immunotherapy? Blood 2003; 102: 23089.
  • 11
    Grizzi F, Chiriva-Internati M, Franceschini B, Hermonat PL, Soda G, Lim SH, Dioguardi N. Immunolocalization of sperm protein 17 in human testis and ejaculated spermatozoa. J Histochem Cytochem. 2003; 51: 12458.
  • 12
    Grizzi F, Chiriva-Internati M, Franceschini B, Bumm K, Colombo P, Ciccarelli M, Donetti E, Gagliano N, Hermonat PL, Bright RK, Gioia M, Dioguardi N, et al. Sperm protein 17 is expressed in somatic ciliated epithelia. J Histochem Cytochem 2004; 52: 54954.
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    Ostrowski LE, Blackburn K, Radde KM, Moyer MB, Schlatzer DM, Moseley A, Boucher RC. A proteomic analysis of human cilia: identification of novel components. Mol Cell Proteomics 2002; 1: 45165.
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    Ibanez-Tallon I, Heintz N, Omran H. To beat or not to beat: roles of cilia in development and disease. Hum Mol Genet 2003; 12: 2735.
  • 15
    O'Rand MG, Widgren EE, Fisher SJ. Characterization of the rabbit sperm membrane autoantigen, RSA, as a lectin-like zona binding protein. Dev Biol 1988; 129: 23140.
  • 16
    Franceschini B, Grizzi F, Colombo P, Soda G, Bumm K, Hermonat Pl, Monti M, Dioguardi N, Chiriva-Internati M. Expression of human sperm protein 17 in melanophages of cutaneous melanocytic lesions. Br J Dermatol 2004; 150: 7802.

Fabio Grizzi, Barbara Franceschini, Paul L. Hermonat, Yong Liu, Maurizio Chiriva-Internati