GPNMB-Positive Cells in Head and Neck Squamous Cell Carcinoma—Their Roles in Cancer Stemness, Therapy Resistance, and Metastasis

Abstract

Objective: Despite the use of surgical and chemoradiation therapies, head and neck squamous cell carcinoma (HNSCC) still has a poor prognosis. Immune checkpoint inhibitors have been shown to prolong life expectancy but have limited efficacy. Glycoprotein nonmetastatic melanoma protein B (GPNMB) has received significant attention in breast cancer treatment, in which it has been associated with cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT); however, the function of GPNMB in HNSCC is completely unknown. This study aimed to clarify the characteristics of GPNMB-positive cells in vitro and their association with the prognosis by immunostaining clinical specimens.Methods: We examined the sphere formation, invasion, and migration ability of GPNMB-positive cells in four HNSCC cell lines in vitro. We also immunostained biopsy specimens with GPNMB from 174 patients with HNSCC diagnosed, treated, and followed-up in our institution to evaluate overall survival and progression-free survival.Results: GPNMB-positive cells showed enhanced sphere formation, invasion, and migration, suggesting that they could have CSC characteristics and the ability to induce EMT, as reported for breast cancer. Clinical specimens showed that overall survival was 39.4% and 57.8% (p = 0.045) and that progression-free survival was 27.6% and 51.6% (p = 0.013) for the high-expression and the low-expression groups, respectively, indicating poor prognosis for the high GPNMB group. The high GPNMB group was also more resistant to chemoradiation and bioradiotherapy. GPNMB was more highly expressed in metastatic lymph nodes than in the primary tumor.Conclusion: GPNMB-positive cells might have CSC characteristics and induce EMT. Detailed functional analyses of GPNMB in HNSCC and the establishment of therapies targeting GPNMB will lead to improved prognoses.

Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma

“…This could be astrocytes or a subgroup of glioma cells. For breast and Head and Neck Squamous Cell carcinoma it has been reported that a subgroup of cancer stem cells express GPNMB and utilize it to persist [ 22 , 46 , 47 ]. Whether GPNMB + IBA1 − cells are these cancer stem cells remains an open issue.…”

GPNMB Expression Associates with Inferior Prognosis in Patients with Small Cell Lung Cancer

“…GPNMB has been implicated in the promotion of cancer cell metastasis through multiple mechanisms. Prior research has identified GPNMB as a crucial molecular mediator that facilitates the acquisition of aggressive traits by inducing matrix metalloproteinases (MMPs) and epithelialmesenchymal transition (EMT) [31][32][33]. Additionally, GPNMB, known for its role as a negative regulator of T cell activation, exhibits potent immunosuppressive properties in the context of cancer [11].…”

Digital spatial profiling of the microenvironment of muscle invasive bladder cancer

“…Notably, immune infiltration, EGFR signalling, STAT3 and hypoxia have all been linked to basal subtypes [22][23][24][25][26][27] , suggesting that GPNMB may play a role in stimulating angiogenesis in basal tumours. GPNMB is a glycoprotein that has been shown to promote the aggressiveness of multiple cancer types, including bladder cancer [28][29][30] . While we found no significant prognostic evidence when analysing GPNMB RNA levels in bulk sequencing, high GPNMB levels measured by immunohistochemistry in bladder cancer was previously correlated with a worse prognosis 29 .…”