Mitigation of Tumor-Associated Fibroblast-Facilitated Head and Neck Cancer Progression With Anti–Hepatocyte Growth Factor Antibody Ficlatuzumab

Abstract

IMPORTANCE Ficlatuzumab can be used to treat head and neck squamous cell carcinoma (HNSCC) by inhibiting c-Met receptor-mediated cell proliferation, migration, and invasion. OBJECTIVE To understand the effect of ficlatuzumab on HNSCC proliferation, migration, and invasion. DESIGN, SETTING, AND PARTICIPANTS The effects of ficlatuzumab on HNSCC proliferation, invasion, and migration were tested. Mitigation of c-Met and downstream signaling was assessed by immunoblotting. The tumor microenvironment has emerged as an important factor in HNSCC tumor progression. The most abundant stromal cells in HNSCC tumor microenvironment are tumor-associated fibroblasts (TAFs). We previously reported that TAFs facilitate HNSCC growth and metastasis. Furthermore, activation of the c-Met tyrosine kinase receptor by TAF-secreted hepatocyte growth factor (HGF) facilitates tumor invasion. Ficlatuzumab is a humanized monoclonal antibody that sequesters HGF, preventing it from binding to and activating c-Met. We hypothesized that targeting the c-Met pathway with ficlatuzumab will mitigate TAF-mediated HNSCC proliferation, migration, and invasion. Representative HNSCC cell lines HN5, UM-SCC-1, and OSC-19 were used in these studies. EXPOSURES FOR OBSERVATIONAL STUDIES The HNSCC cell lines were treated with ficlatuzumab, 0 to 100 µg/mL, for 24 to 72 hours. MAIN OUTCOMES AND MEASURES Ficlatuzumab inhibited HNSCC progression through c-Met and mitogen-activated protein kinase (MAPK) signaling pathway. RESULTS Ficlatuzumab significantly reduced TAF-facilitated HNSCC cell proliferation (HN5, P< .001; UM-SCC-1, P< .001), migration (HN5, P = .002; UM-SCC-1, P = .01; and OSC-19, P = .04), and invasion (HN5, P = .047; UM-SCC-1, P = .03; and OSC-19, P = .04) through a 3-dimensional peptide-based hydrogel (PGmatrix). In addition, ficlatuzumab also inhibited the phosphorylation of c-Met at Tyr1234/1235 and p44/42 MAPK in HNSCC cells exposed to recombinant HGF. CONCLUSIONS AND RELEVANCE We demonstrate that neutralizing TAF-derived HGF with ficlatuzumab effectively mitigates c-Met signaling and decreases HNSCC proliferation, migration, and invasion. Thus, ficlatuzumab effectively mitigates stromal influences on HNSCC progression.

Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis

“…In organotypic assays, HGF released by CAFs promoted invasion of esophageal squamous cell carcinoma cells, which could be inhibited by siRNAs targeting HGF in fibroblasts or by altering c-Met expression or function in carcinoma cells [19]. Similarly, impairment of the HGF–cMet interaction with the monoclonal antibody ficlatuzumab inhibited head and neck squamous cell carcinoma (HNSCC) cell migration and invasion in response to treatment with CAF-conditioned media [20]. Intriguingly, when HNSCC cells were injected with CAFs into the floor of the mouth of athymic mice, much larger tumors were formed, compared with cancer cells alone, and increased metastasis to lungs and regional lymph nodes was observed.…”

Early Events in Actin Cytoskeleton Dynamics and E-Cadherin-Mediated Cell-Cell Adhesion during Epithelial-Mesenchymal Transition

“…EMT can be triggered by TGF-β, EGF, HGF, and FGF produced by stromal cells [17][18][19][20]. HGF and TGF-β secretion by cancer-associated fibroblasts activated migration of carcinoma cells [21,22]. Highly dynamic EMT was described during tumor cell intravasation stimulated by tumor-associated macrophages that produced EGF and thereby activated migration of tumor cells [18,23].…”

Immortal Life of the Common Rule: Ethics, Consent, and the Future of Cancer Research

“…The donors for University of Michigan (UM) Squamous Carcinoma cell lines (SCC)-1 through UM-SCC-81 are all deceased, most within 2 years of tissue procurement, and UM-SCC-1 is still being routinely used by researchers throughout the world. [21][22][23] In addition, at a tertiary care center, many patients transition their care back within their community and may be lost to follow-up. Thus, it would be difficult, if not impossible, to contact and reconsent individuals after 10 years.…”