Carcinoma-associated Fibroblasts are a Common Finding in the Microenvironment of HPV-positive Oropharyngeal Squamous Cell Carcinoma

Abstract

The important role of the human papillomavirus (HPV) is widely established in oropharyngeal squamous cell carcinoma (OPSCC). The behavior of a OPSCCs especially induced by HPV might be influenced by the tissue microenvironment and its changes according to the tumor nature. Recognition of the role of the tumor microenvironment on the behavior of neoplastic cells has led to utilization of the microenvironment to use as therapeutic target. Carcinoma-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, show wide-spread expression of alpha-smooth muscle actin (α-SMA). We focused on CAFs, its presence in OPSCC and the relationship with HPV for the first time. Expression of α-SMA protein in CAFs of the tumor microenvironment of the 44 formalin-fixed paraffin-embedded tissue blocks from the primary tumor of OPSCC evaluated by immunohistochemistry between HPV-positive and HPV-negative tumors separated by nested polymerase chain reaction. In 44 samples 23 HPV-positive cases were detected. Statistically there were significant differences between histopathologic grade, percent and final score of α-SMA and HPV expression. Significant difference between HPV expression and inflammation, intensity, and clinical parameters was not identified in the present study. Our results indicate that CAFs are a common finding in the microenvironment of HPV-positive OPSCC and associated with higher histopathologic grade. Therapeutic strategies to use CAF-mediated drugs need to be considered and evaluated more for treatment of HPV-positive OPSCC.

Analysis of cells of epithelial, connective tissue and immune differentiation in HPV-positive-, HPV-negative oropharyngeal carcinoma and normal oropharyngeal tissue by immunofluorescence multiplex image cytometry: a preliminary report

“…The lower percentage of connective tissue cells in tumor cell clusters of patients with HPV + OPSCC (Table 5 ) may be associated with a lower fibroblast response compared to patients with HPV-OPSCC. This observed “desmoplastic reaction” supports cancer migration and invasion in vitro, as reported by Bolt [ 9 ] and Rahrotaban [ 37 ]. In contrast, a higher percentage of connective tissue cells was identified in the stroma of HPV + compared to HPV- OPSCC samples (Table 5 ), as described by Mohamed and coauthors [ 38 ].…”

Fibroblasts from HPV-negative oropharynx squamous cell carcinomas stimulate the release of osteopontin from cancer cells via the release of IL-6

“…The role of fibroblasts in the tumour microenvironment of OPSCC has been understudied, even when compared to those at other sites within the head and neck. Others have shown that CAFs are frequently identified in the TME of HPV+ OPSCC (23), but, in general, the data (IHC and sequencing) suggests higher fibroblast signatures in HPV-negative OPSCC when compared with HPV-positive OPSCC (18). The data which we have generated from the assessment of the OPSCC TMAs would bear this out (Figure 1).…”

PLOD2 increases resistance of gastric cancer cells to 5-fluorouracil by upregulating BCRP and inhibiting apoptosis

“…The ECM is produced by multiple TME cell types and weaves an intricate fiber network not only providing structural support but also regulating the physical and biochemical properties of the tumor microenvironment, thereby regulating the polarity, migration and signaling of cancer cells [24]. The tumor microenvironment not only plays a key role in tumor progression but also is associated with chemoresistance [25,26]. In breast cancer, attachment of malignant cells to the ECM alters their polarization and causes resistance to etoposide-induced apoptosis [27].…”