ABSTRACT
Oral cancer has become one of the most aggressive types of cancer, killing 140,000 people worldwide every year. Current treatments for oral cancer include surgery and radiation therapies. These procedures can be very effective; however, they can also drastically decrease the quality of life for survivors. New chemotherapeutic treatments are needed to more effectively combat oral cancer. The transmembrane receptor podoplanin (PDPN) has emerged as a functionally relevant oral cancer biomarker and chemotherapeutic target. PDPN expression promotes tumor cell migration leading to oral cancer invasion and metastasis. Here, we describe the role of PDPN in oral squamous cell carcinoma progression, and how it may be exploited to prevent and treat oral cancer.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Membrane Glycoproteins/metabolism , Mouth Neoplasms/metabolism , Animals , Carcinoma, Squamous Cell/pathology , Humans , Mouth Neoplasms/pathologyABSTRACT
Podoplanin (PDPN) is a unique transmembrane receptor that promotes tumor cell motility. Indeed, PDPN may serve as a chemotherapeutic target for primary and metastatic cancer cells, particularly oral squamous cell carcinoma (OSCC) cells that cause most oral cancers. Here, we studied how a monoclonal antibody (NZ-1) and lectin (MASL) that target PDPN affect human OSCC cell motility and viability. Both reagents inhibited the migration of PDPN expressing OSCC cells at nanomolar concentrations before inhibiting cell viability at micromolar concentrations. In addition, both reagents induced mitochondrial membrane permeability transition to kill OSCC cells that express PDPN by caspase independent nonapoptotic necrosis. Furthermore, MASL displayed a surprisingly robust ability to target PDPN on OSCC cells within minutes of exposure, and significantly inhibited human OSCC dissemination in zebrafish embryos. Moreover, we report that human OSCC cells formed tumors that expressed PDPN in mice, and induced PDPN expression in infiltrating host murine cancer associated fibroblasts. Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Squamous Cell/pathology , Membrane Glycoproteins/antagonists & inhibitors , Molecular Targeted Therapy , Mouth Neoplasms/pathology , Neoplasm Proteins/antagonists & inhibitors , Phytohemagglutinins/pharmacology , Administration, Oral , Animals , Animals, Genetically Modified , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Squamous Cell/virology , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Fibroblasts/pathology , Humans , Membrane Glycoproteins/immunology , Membrane Glycoproteins/physiology , Membrane Potential, Mitochondrial/drug effects , Mice , Mouth Neoplasms/virology , Neoplasm Proteins/immunology , Neoplasm Proteins/physiology , Papillomaviridae/isolation & purification , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Phytohemagglutinins/administration & dosage , Phytohemagglutinins/therapeutic use , Xenograft Model Antitumor Assays , Zebrafish/embryologyABSTRACT
Podoplanin (PDPN) is a transmembrane receptor that affects the activities of Rho, ezrin, and other proteins to promote tumor cell motility, invasion, and metastasis. PDPN is found in many types of cancer and may serve as a tumor biomarker and chemotherapeutic target. The intracellular region of PDPN contains only two serines, and these are conserved in mammals including mice and humans. We generated cells from the embryos of homozygous null Pdpn knock-out mice to investigate the relevance of these serines to cell growth and migration on a clear (PDPN-free) background. We report here that one or both of these serines can be phosphorylated by PKA (protein kinase A). We also report that conversion of these serines to nonphosphorylatable alanine residues enhances cell migration, whereas their conversion to phosphomimetic aspartate residues decreases cell migration. These results indicate that PKA can phosphorylate PDPN to decrease cell migration. In addition, we report that PDPN expression in fibroblasts causes them to facilitate the motility and viability of neighboring melanoma cells in coculture. These findings shed new light on how PDPN promotes cell motility, its role in tumorigenesis, and its utility as a functionally relevant biomarker and chemotherapeutic target.