Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor‐associated fibroblasts in preclinical models

Abstract

Background Head and neck squamous cell carcinoma (HNSCC) has had little improvement in mortality rates in decades. A clearer understanding of the HNSCC tumor microenvironment will aid in finding more effective targeted therapies for this disease. Tumor associated fibroblasts (TAFs) are the largest stromal cellular components of the tumor microenvironment in HNSCC. Methods We isolated TAFs from clinical HNSCC cases and propagated in vitro. The effects of TAF secreted paracrine factors on in vitro HNSCC migration, invasion and proliferation was assessed. The effect of TAFs on HNSCC growth and metastases was determined in an orthotopic floor of mouth tumor model. Results TAF conditioned media increased HNSCC cell migration, invasion and proliferation. TAFs increased HNSCC tumor growth and metastases in vivo. Conclusions TAFs play a major role in increasing tumor growth and metastasis in HNSCC. Targeting the tumor stroma may be important to reduce the rate of HNSCC metastasis.

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

“…Notably, Src is activated both as a consequence of EGFR signaling and as a precursor to EGFR signaling when G-coupled protein receptors recruit pSrc to the upstream complex mediating EGFR transactivation (18,32,34). In preclinical HNSCC models, activation of Src causes resistance to EGFR inhibition (19,35,36). In patients with HNSCC, elevated baseline pSrc expression was associated with resistance to the antiproliferative effects of erlotinib during our first window trial (37).…”

Mechanisms of Invasion in Head and Neck Cancer

“…[234][235][236][237] Myofibroblasts and cancerassociated fibroblasts have been shown to enhance HNSCC invasion in vitro in a variety of assays. [238][239][240][241][242][243][244][245][246][247] Treatments that can enhance the ability of fibroblasts to stimulate tumor cell invasion include irradiation 182 and reactive oxygen species, 183,248,249 as well as lifestyle-correlated factors, such as cigarette smoke 250 and areca nut extract. 251 Fibroblasts have been shown to stimulate tumor cell invasion through secretion of a number of factors, including chemokine (C-C motif) ligand 2 (CCL2), 183,252 260 and hepatocyte growth factor (HGF).…”

Tumor Microenvironment in Head and Neck Squamous Cell Carcinomas

“…CAFs located in tumor stromal microenvironment play a critical role; they are particularly effective in carcinogenesis, tumor progression, and metastasis (29,30). In the CAF activity study, which they conducted with the samples taken from the head and neck cancer tumor stroma, Rosenthal et al (31) revealed that CAFs play an important role in the production of many protease enzymes (membrane type 1-matrix metalloproteinase (MMP), MMP1, MMP2, MMP3, MMP9, urokinase, etc.)…”