Chemokine receptors in head and neck cancer: Association with metastatic spread and regulation during chemotherapy

Abstract

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, a-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. ' 2005 Wiley-Liss, Inc.Key words: head and neck cancer; squamous cell carcinoma; adenoid cystic carcinoma; chemokine receptor; metastasis Head and neck carcinomas (HNC) include tumors with different histological phenotypes and distinct clinical characteristics. Squamous cell carcinomas (SCC) of the upper aerodigestive tract mucosa represent the most common histological subtype.

Chemokine CXCL13 is overexpressed in the tumour tissue and in the peripheral blood of breast cancer patients

“…Furthermore, given the elevated CXCL13 expression in the serum of patients with metastatic disease as compared with patients without evidence of tumour burden, this chemokine may also serve as a tumour marker. In our analysis of breast cancer cell lines and tumour samples, we found the expression of chemokine receptor CXCR5 to be restricted to the cytoplasma, a finding that is in line with observations of Muller et al (2006) who detected CXCR5 intracellulary but did not detect surface expression of CXCR5 in cell lines and tumour samples from patients with metastatic head and neck cancer. Although these findings, at first glance, do not support the concept of CXCR5 as the main target for CXCL13 overexpression in breast cancer, we believe that they do not reflect the potential role this chemokine receptor might play in vivo.…”

CXCL12-CXCR4 Promotes Proliferation and Invasion of Pancreatic Cancer Cells

“…A growing number of studies have confirmed that CXCR4 is expressed on the surface of a variety of tumor cells (such as salivary adenoid cystic carcinoma, breast cancer, and oral squamous carcinoma cells). It interacts with its corresponding chemokines, including CXCL12, and the molecular pair then influences the biological behavior of tumor cells (Muller et al, 2006;Kato et al, 2003;Almofti et al, 2004). We found here that, although pancreatic cancer cells do not themselves express CXCL12, they do express CXCR4 which was confirmed by immunoblotting mehhod (Grzesiak et al 2007); therefore, these cells are capable of responding to chemotactic signals from CXCL12.…”

Beyond tumorigenesis: cancer stem cells in metastasis

“…Molecular crosstalk between the primary tumor and the pre-metastasis niche through secreted stimulatory signals helps govern the homing of mCSCs. Trafficking towards preferred tissues and organs of mCSCs is guided by cues such as oxygen gradients or other chemo-attractants derived from niche sites [94,[123][124][125].…”