Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Evidence that activin A upregulates selected chemokines and metalloproteinases to influence human testicular cancer (#31)

Maciej Szarek 1 2 3 4 , Martin Burgmann 4 5 , Lutz Konrad 3 4 , Hans-Christian Shuppe 4 5 , Kate L Loveland 1 2 4 6 7
  1. Molecular and Translational Sciences , Monash University , Melbourne, Victoria, Australia
  2. Monash University, Clayton, VIC, Australia
  3. Frauenheilkunde und Geburtshilfe, Justus Liebig University , Giessen, Hessen, Germany
  4. International Research Training Group, Melbourne and Giessen
  5. Histology and Embryology , Justus Liebig University , Giessen, Hessen, Germany
  6. Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
  7. Hudson Institute of Medical Research , Melbourne, Victoria , Australia

The rate of seminoma and non-seminoma is increasing, particularly in Australia and Western Europe. These tumours of young men originate from carcinoma in situ (CIS) cells, which are hypothesized to arise from dysfunctional gonocytes during foetal development. Signals that govern CIS cell development remain unknown, although, activin A, a pleiotropic growth factor in the TGFβ superfamily, may be involved. Immunohistochemical analysis of human adult testes and seminomas, showed that activin signalling moieties localise to Sertoli cells (SC), spermatogonia and seminoma cells, suggesting these cells can respond to activin A. Activin affects both the somatic cells and the germ cells in the juvenile mouse testis, therefore, activin A may influence stages of human testicular cancer. The chemotactic cytokines, CXCL12, CCL17, their receptors, CXCR4, CCR4, CXCR7, and the metalloproteinases, MMP2 and MMP9, are upregulated by activin A and are involved in cancer metastasis. However, the functions of these in the testis are unknown. We hypothesized activin A influences the production of CXCL12, CCL17, MMP2 and MMP9 to stimulate testicular cancer metastasis. Using paraffin-embedded human testicular biopsies, antibodies to CXCL12 stained SC cytoplasm in both normal and CIS-containing tubules. CCL17 immunoreactivity was present within the SC cytoplasm of CIS-containing tubules but not in normal tissue. Exposure of TCam-2 cells (human seminoma line) to high dose CCL17 (200 ng/mL) promoted migration through simulated basement membranes (Transwell assay). Pretreating TCam-2 cells with activin A (5 ng/mL and 50 ng/mL) for 24 hours significantly upregulated CXCR4 and CXCR7 transcripts (n=5, P<0.05) and resulted in increased MMP2 but not MMP9 secretion (n=5, p<0.01). These findings suggest activin A may modulate seminoma cell behaviour by altering selected chemokines and metalloproteinases. Understanding the factors that influence the development of a tumorigenic phenotype of the testis may help facilitate fertility-sparing therapeutics.