Calprotectin and the Initiation and Progression of Head and Neck Cancer

Abstract

Calprotectin (S100A8/A9), a heterodimeric complex of calcium-binding proteins S100A8 and S100A9, is encoded by genes mapping to the chromosomal locus 1q21.3 of the epidermal differentiation complex. Whereas extracellular calprotectin shows proinflammatory and antimicrobial properties by signaling through RAGE and TLR4, intracytoplasmic S100A8/A9 appears to be important for cellular development, maintenance, and survival. S100A8/A9 is constitutively expressed in myeloid cells and the stratified mucosal epithelia lining the oropharyngeal and genitourinary mucosae. While upregulated in adenocarcinomas and other cancers, calprotectin mRNA and protein levels decline in head and neck squamous cell carcinoma (HNSCC). S100A8/A9 is also lost during head and neck preneoplasia (dysplasia). Calprotectin decrease does not correlate with the clinical stage (TNM) of HNSCC. When expressed in carcinoma cells, S100A8/A9 downregulates matrix metalloproteinase 2 expression and inhibits invasion and migration in vitro. S100A8/A9 regulates cell cycle progression and decelerates cancer cell proliferation by arresting at the G2/M checkpoint in a protein phosphatase 2α-dependent manner. In HNSCC, S100A8 and S100A9 coregulate with gene networks controlling cellular development and differentiation, cell-to-cell signaling, and cell morphology, while S100A8/A9 appears to downregulate expression of invasion- and tumorigenesis-associated genes. Indeed, tumor formation capacity is attenuated in S100A8/A9-expressing carcinoma cells in vivo. Hence, intracellular calprotectin appears to function as a tumor suppressor in head and neck carcinogenesis. When compared with S100A8/A9-low HNSCC based on analysis of TCGA, S100A8/A9-high HNSCC shows significant upregulation of apoptosis-related genes, including multiple caspases. Accordingly, S100A8/A9 facilitates DNA damage responses in HNSCC, promotes apoptotic cell death, and confers sensitivity to cisplatin and X-radiation in vitro. In the tumor milieu, loss of S100A8/A9 strongly associates with poor squamous differentiation and higher tumor grading, EGFR upregulation, increased DNA methylation, and, finally, poorer overall survival for patients with HNSCC. Hence, intracellular calprotectin shows a multifaceted protective role against the development of HNSCC.

Expressions of extracellular matrix‐remodeling factors in lymph nodes from oral cancer patients

“…As for S100A8, we did not detect a correlation between lymphatic metastasis and the expression in SCC cells and stromal cells. In contrast to LOX, MT1-MMP, and TIMP-1, declining expression of S100A8 in head and neck primary SCC indicated worse prognosis (Argyris et al, 2018;Khammanivong et al, 2016). Argyris et al showed that S100A8/A9 complex (calprotectin) downregulated MMP-2 expression, which inhibited invasion and migration of cancer cells in vitro (Argyris et al, 2018).…”

“…In contrast to LOX, MT1-MMP, and TIMP-1, declining expression of S100A8 in head and neck primary SCC indicated worse prognosis (Argyris et al, 2018;Khammanivong et al, 2016). Argyris et al showed that S100A8/A9 complex (calprotectin) downregulated MMP-2 expression, which inhibited invasion and migration of cancer cells in vitro (Argyris et al, 2018). Conversely, Choi et al demonstrated that overexpression of S100A8 and S100A9 increased tumor growth and volume in cutaneous SCC (Choi et al, 2014).…”

“…ECM-remodeling factors and whether they play a role in the lymphatic metastasis are unknown. Thus, we investigated correlation between lymphatic metastasis of OSCC and the expression of ECM-remodeling factors, such as LOX (lysyl oxidase), MT1-MMP (membrane type MMP-1) also known as MMP-14, S100A8 (S100 calcium-binding protein A8) and TIMP-1 (tissue inhibitor of metalloproteinases-1) in OSCC cells and surrounding inflammatory cells and stromal fibroblasts (Albinger-Hegyi et al, 2010;Argyris, Slama, Ross, Khammanivong, & Herzberg, 2018;Bodnar, Szylberg, Kazmierczak, & Marszalek, 2015;Khammanivong et al, 2016;Le et al, 2009;Myoung et al, 2002;Perez-Sayans Garcia et al, 2012;Zhang, Liu, Sun, & Lu, 2009).…”

<p>The Blood Biomarkers of Thyroid Cancer</p>

“…In addition to anaplastic thyroid carcinoma, it has no significant role in non-neoplastic thyroid tissue and well-differentiated thyroid tumors. 35 And as an important proinflammatory factor, platelets have also been studied as a biomarker. It will be rather convenient if the platelets could be the marker, since the test of it is such regular.…”

“…In addition to anaplastic thyroid carcinoma, it has no significant role in non-neoplastic thyroid tissue and well-differentiated thyroid tumors. 35 …”