Crosstalk between head and neck cancer cells and lymphatic endothelial cells promotes tumor metastasis via CXCL5‐CXCR2 signaling

Head and neck squamous cell carcinoma (HNSCC) metastasizes to the locoregional lymph nodes at high rates and is related to poor clinical outcomes. However, the mechanism by which cancer cells migrate to the lymph nodes is unclear. To address this, we established a conditioned medium culture system for HNSCC cells and lymphatic endothelial cells (LECs) and investigated their crosstalk. Stimulation with tumor‐conditioned medium (TCM) activated LECs, resulting in a robust increase in cell proliferation to induce lymphatic hyperplasia. Further, stimulation of HNSCC cells with activated LEC Conditioned media (TCM‐LEC CM) induced cell invasion. Among various chemokines, CXCL5 promoted the invasion of TCM‐LEC CM‐treated HNSCC cells. The level of CXCL5 protein was higher in cancer tissues than those in normal tissues from HNSCC patients. Furthermore, treatment with SB225002, a CXCR2 (CXCL5 receptor) inhibitor, resulted in decreased lymph node metastasis in vivo. In conclusion, inhibition of CXCL5‐CXCR2 signaling between cancer cells and LECs suppresses cancer cell invasion and metastasis in vitro and in vivo. This novel therapeutic strategy might be a practical approach to the clinical management of HNSCC.

[1]  Wei Li,et al.  CXCL5 promotes gastric cancer metastasis by inducing epithelial-mesenchymal transition and activating neutrophils , 2020, Oncogenesis.

[2]  L. Chow.  Head and Neck Cancer. , 2020, The New England journal of medicine.

[3]  G. Niebur,et al.  The CXCL5/CXCR2 axis is sufficient to promote breast cancer colonization during bone metastasis , 2019, Nature Communications.

[4]  Xia-Wei Wei,et al.  Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. , 2019, Biochimica et biophysica acta. Reviews on cancer.

[5]  Shu-ren Ma,et al.  CXCL5, the upregulated chemokine in patients with uterine cervix cancer, in vivo and in vitro contributes to oncogenic potential of Hela uterine cervix cancer cells. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[6]  T. Kang,et al.  The CXCL5/CXCR2 axis contributes to the epithelial-mesenchymal transition of nasopharyngeal carcinoma cells by activating ERK/GSK-3β/snail signalling , 2018, Journal of experimental & clinical cancer research : CR.

[7]  Jie Gu,et al.  CXCL5 regulation of proliferation and migration in human non-small cell lung cancer cells , 2018, Journal of Physiology and Biochemistry.

[8]  Qingyuan Zhang,et al.  CXCL5 secreted from adipose tissue-derived stem cells promotes cancer cell proliferation , 2017, Oncology letters.

[9]  Y. Zong,et al.  Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways , 2017, Molecular Cancer.

[10]  lin zhou,et al.  Neutrophil infiltration mediated by CXCL5 accumulation in the laryngeal squamous cell carcinoma microenvironment: A mechanism by which tumour cells escape immune surveillance. , 2017, Clinical immunology.

[11]  S. Cai,et al.  CXCL1 from tumor-associated lymphatic endothelial cells drives gastric cancer cell into lymphatic system via activating integrin β1/FAK/AKT signaling. , 2017, Cancer letters.

[12]  A. Biankin,et al.  CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma , 2016, Cancer cell.

[13]  A. Garden,et al.  Relation between the level of lymph node metastasis and survival in locally advanced head and neck squamous cell carcinoma , 2016, Cancer.

[14]  Y. Ko,et al.  Prediction of Lymph Node Metastasis by Tumor Dimension Versus Tumor Biological Properties in Head and Neck Squamous Cell Carcinomas , 2015, Cancer research and treatment : official journal of Korean Cancer Association.

[15]  Xin-yang Wang,et al.  CXCL5/CXCR2 axis promotes bladder cancer cell migration and invasion by activating PI3K/AKT-induced upregulation of MMP2/MMP9. , 2015, International journal of oncology.

[16]  D. Nicholls,et al.  Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist , 2015, The Journal of Pharmacology and Experimental Therapeutics.

[17]  A. Popel,et al.  Lymphatic endothelial cells support tumor growth in breast cancer , 2014, Scientific Reports.

[18]  S. Sukumar,et al.  Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis , 2014, Nature Communications.

[19]  Michael Detmar,et al.  Mechanisms of lymphatic metastasis. , 2014, The Journal of clinical investigation.

[20]  S. Stacker,et al.  Lymphangiogenesis and lymphatic vessel remodelling in cancer , 2014, Nature Reviews Cancer.

[21]  E. Tsai,et al.  Breast tumor-associated osteoblast-derived CXCL5 increases cancer progression by ERK/MSK1/Elk-1/Snail signaling pathway , 2013, Oncogene.

[22]  A. Popel,et al.  Pre-treatment of mice with tumor-conditioned media accelerates metastasis to lymph nodes and lungs: a new spontaneous breast cancer metastasis model , 2013, Clinical & Experimental Metastasis.

[23]  M. Detmar,et al.  Interaction of tumor cells and lymphatic vessels in cancer progression , 2012, Oncogene.

[24]  S. Cai,et al.  Lymphatic endothelial cell‐secreted CXCL1 stimulates lymphangiogenesis and metastasis of gastric cancer , 2012, International journal of cancer.

[25]  Liang Han,et al.  High expression of CXCR2 is associated with tumorigenesis, progression, and prognosis of laryngeal squamous cell carcinoma , 2012, Medical Oncology.

[26]  K. Alitalo,et al.  The lymphatic vasculature in disease , 2011, Nature Medicine.

[27]  D. Nam,et al.  CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. , 2010, Cancer research.

[28]  R. Strieter,et al.  CXC chemokines in cancer angiogenesis and metastases. , 2010, Advances in cancer research.

[29]  W. Westra,et al.  Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. , 2009, Annual review of pathology.

[30]  M. Skobe,et al.  Lymphatic Vessel Activation in Cancer , 2002, Annals of the New York Academy of Sciences.

[31]  C. Borel,et al.  Prognostic indicators for survival in head and neck squamous cell carcinomas: Analysis of a series of 621 cases , 2005, Head & neck.

[32]  Adrian L Harris,et al.  Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. , 2002, Cancer research.

[33]  D. Graves,et al.  Chemokines, a family of chemotactic cytokines. , 1995, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[34]  G. Snow,et al.  Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma , 1993, Cancer.

[35]  L. Cerezo,et al.  Prognostic factors for survival and tumor control in cervical lymph node metastases from head and neck cancer: A multivariate study of 492 cases , 2010, Cancer.

[36]  S. Taylor.  Head and neck cancer. , 1991, Cancer chemotherapy and biological response modifiers.

[37]  J. Shah,et al.  Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. , 1990, American journal of surgery.