Chemokine receptors in head and neck cancer: association with metastatic spread and regulation during chemotherapy.
Head and neck carcinomas are histologically and clinically heterogeneous. While squamous cell carcinomas (SCC) are characterized by lymphogenous spread, adenoid cystic carcinomas (ACC) disseminate preferentially hematogenously. To study cellular and molecular mechanisms of organ-specific metastasis, we used SCC and ACC cell lines and tumor tissues, obtained from patients with primary or metastatic disease. Comprehensive analysis at the mRNA and protein level of human chemokine receptors showed that SCC and ACC cells exhibited distinct and nonrandom expression profiles for these receptors. SCC predominantly expressed receptors for chemokines homeostatically expressed in lymph nodes, including CC chemokine receptor (CCR) 7 and CXC chemokine receptor (CXCR)5. No difference in expression of chemokine receptors was seen in primary SCC and corresponding lymph node metastases. In contrast to SCC, ACC cells primarily expressed CXCR4. In chemotaxis assays, ACC cells were responsive to CXCL12, the ligand for CXCR4. Exposure of ACC cells to cisplatin resulted in upregulation of CXCR4 on the cell surface, which was repressed by the transcriptional inhibitor, alpha-amanitin. Treatment of ACC cells with CXCL12 resulted in the activation of Akt and ERK1/2 pathways. Furthermore, CXCL12 suppressed the rate of apoptosis induced by cisplatin in ACC cells, suggesting that signaling via CXCR4 may be part of a tumor cell survival program. Discrimination of the chemokine receptor profile in SCC and ACC in vitro and in tissues provided insights into their distinct biologic and clinical characteristics as well as indications that chemokine receptors might serve as future therapeutic targets in these malignancies.
Muller
Anja
A
Department of Radiation Oncology, Heinrich-Heine-University, Duesseldorf, Germany. a.mueller@uni-duesseldorf.de
Sonkoly
Eniko
E
Eulert
Christine
C
Gerber
Peter Arne
PA
Kubitza
Robert
R
Schirlau
Kerstin
K
Franken-Kunkel
Petra
P
Poremba
Christopher
C
Snyderman
Carl
C
Klotz
Lars-Oliver
LO
Ruzicka
Thomas
T
Bier
Henning
H
Zlotnik
Albert
A
Whiteside
Theresa L
TL
Homey
Bernhard
B
Hoffmann
Thomas K
TK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D003528:Carcinoma, Adenoid Cystic / Q000556:secondary*; D002294:Carcinoma, Squamous Cell / Q000556:secondary*; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000032:analysis; D019707:Receptors, Chemokine / Q000032:analysis* / Q000096:biosynthesis; D015398:Signal Transduction
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D002945:Cisplatin