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S.C.D.U. Medical Oncology I.R.C.C. Candiolo Ordine Mauriziano

CXCR4 receptor is correlated to the development of metastases in leiomyosarcoma, pleomorphic sarcoma and liposarcoma. S Aliberti, G Grignani, G Cavalloni, A Pisacane, P Allione, I Sarotto, Y Pignochino, M Motta, B Torchio, M Risio, M Aglietta. S.C.D.U. Medical Oncology I.R.C.C. Candiolo

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S.C.D.U. Medical Oncology I.R.C.C. Candiolo Ordine Mauriziano

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  1. CXCR4 receptor is correlated to the development of metastases in leiomyosarcoma, pleomorphic sarcoma and liposarcoma S Aliberti, G Grignani, G Cavalloni, A Pisacane, P Allione, I Sarotto, Y Pignochino, M Motta, B Torchio, M Risio, M Aglietta. S.C.D.U. Medical Oncology I.R.C.C. Candiolo Ordine Mauriziano

  2. “When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.” S Paget The Lancet 1889

  3. -3149 adult patients with soft tissue sarcoma were admitted and treated at Memorial Sloan-Kettering Cancer Center. -719 patients developed lung metastases (about 24%)

  4. Tumor progression steps

  5. Non-target tissue endothelium different chemokine Y Y Cancer cell Target tissue endothelium chemokine Y chemokine receptor Y Cancer cell

  6. Involvement of CXCR4/SDF-1 system in cancer progression

  7. Purpose • To analyze expression patterns of CXCR4, EGFR, angioinvasiveness (by standard immunohistochemical technique) along with other primary tumor features (T and grading). • To assess if there is a correlation among the characteristics of primary tumor and the development of metastases.

  8. Materials and methods We retrospectivelyevaluated expression patterns of CXCR4, EGFR and angioinvasiveness features on primary tumors in 67 pts. -Mean age = 57 yrs (24 - 85) -Male/female = 38/29 -Median follow-up = 57 mos (2 – 160) -Limbs/retroperitoneal = 47/20 -Histotype: leiomyosarcoma, pleomorphic sarcoma non-myxoid liposarcoma. -Grading: according to Coindre et al.

  9. Materials and methods

  10. CXC4 immunohistochemistry Cytoplasmic positivity Nuclear positivity CXCR4: Pharmagin 12G-5 monoclonal antibody

  11. EGFR immunohistochemistry Negative = 0/1+ & < 1% of cells Positive = 3+ & 80% of cells EGFR: pharmaDx monoclonal antibody DakoCytomation

  12. Angioinvasiveness features

  13. Results Angio- Invasiveness CXCR4 EGFR

  14. Univariate Multivariate 0.017 0.02 0.32 0.018 0.06 0.05 0.03 0.07 0.067 Correlation with development of metastases

  15. Response according to metastasis

  16. CXCR4 - stratified by grading CXCR4 neg p = 0.05 CXCR4 neg CXCR4 pos CXCR4 pos p = 0.018 Grade = 1 or 2 Grade = 3

  17. Where do we go from here?

  18. CXCR4 expression on leiomyosarcoma cell lines

  19. CXCR4 down-regulation by SDF-1 on CXCR4+ leiomyosarcoma cell lines

  20. Regulation of CXCR4 expression by in vitro gene transduction in leiomyosarcoma cell line

  21. AMD3465 selectively reduces CXCR4 transcript expression in lungs.

  22. Conclusions • In this retrospective series we show how CXCR4 is associated with the development of lung metastases. • We are currently verifying these results on larger series. • We are developing an in vitro model in which we can modulate CXCR4 expression. • The metastatic behavior of these histotypes needs further study but we believe CXCR4 may play a role in the recurrence of soft tissue sarcoma.

  23. Acknowledgments Medical Oncology: Sandra Aliberti Paolo Allione Massimo Aglietta Surgical Pathology: Alberto Pisacane Ivana Sarotto Mauro Risio Surgical Pathology: Manuela Motta Bruno Torchio Molecular Oncology: Giuliana Cavalloni Ymera Pignochino

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