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The chemokine CXCL 12 and its receptor CXCR 4 are implicated in human seminoma metastasis
Author(s) -
McIver S. C.,
Loveland K. L.,
Roman S. D.,
Nixon B.,
Kitazawa R.,
McLaughlin E. A.
Publication year - 2013
Publication title -
andrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.947
H-Index - 43
eISSN - 2047-2927
pISSN - 2047-2919
DOI - 10.1111/j.2047-2927.2013.00081.x
Subject(s) - gonocyte , biology , seminoma , cancer research , sertoli cell , stem cell , microbiology and biotechnology , immunology , endocrinology , spermatogenesis , genetics , chemotherapy
Summary Seminoma and non‐seminoma tumours increasingly occur within the western population. These tumours originate from carcinoma in situ ( CIS ) cells, which arise from dysfunctional gonocytes. CXCL 12 and its receptors, CXCR 4 and CXCR 7, have been implicated in migration, proliferation and survival of gonocytes and their precursors and progeny, primordial germ cells and spermatogonial stem cells respectively. We previously found evidence that several mi RNA molecules predicted to modulate CXCR 4 signalling are differentially expressed during the differentiation of gonocytes into spermatogonia in mice. Bioinformatic analysis predicted these mi RNA to modulate CXCR 4 signalling, leading us to hypothesize that CXCL 12‐mediated CXCR 4 signalling is involved in the disrupted differentiation of gonocytes that underpins CIS formation. Indeed, we detected CXCL 12 in Sertoli cells of normal human testis, and relatively high expression in tumour stroma with concomitant weak staining in dispersed tumour cells. In contrast, CXCR 4 was expressed in spermatogonial and meiotic germ cells of normal testis and in the majority of tumour cells. Quantitative RT ‐ PCR identified elevated CXCR 4 transcript levels in seminoma compared with normal testis and to non‐seminoma, potentially reflecting the higher proportion of dysfunctional germ cells within seminomas. In the normal testis, expression of CXCR 4 downstream signalling molecules phospho‐ MEK 1/2 and phospho‐ ERK 1/2 correlated with CXCR 4/ CXCL 12 expression. Strikingly, this correlation was absent in seminoma and non‐seminoma samples, suggesting that CXCL 12 signalling is disrupted. Proliferation rate and cell survival were not altered by CXCL 12 in either seminoma ( TC am‐2) or non‐seminoma (833ke) cell lines. However, CXCL 12 exposure induced TC am‐2 cell invasion though simulated basement membrane, while in contrast, we provide the novel evidence that CXCR 4‐expressing non‐seminoma cell lines 833ke and NT era2/D1 do not invade in response to CXCL 12. These findings indicate that CXCL 12 expression in the human testis may selectively influence seminoma migration and metastasis, correlating with its importance in gonocyte and spermatogonial stem cell biology.