Chapter 6 - Cell Surface GRP78: A Targetable Marker of Cancer Stem-Like Cells

Abstract

Most therapies target proliferating tumor cells, resulting in tumor debulking. However, frequently drug-resistant, residual tumor cells are present and are thought to be responsible for tumor recurrence and patient mortality. Significant data points to the fact that tumors are heterogeneous, being composed of proliferative and nonproliferating tumor cell subpopulations. Frequently, the latter is therapy-resistant and exhibits cancer stem-like properties. Glucose Regulated Protein of 78kDa (GRP78) has been implicated in both drug resistance and in stem-like cell behaviors, and has been shown to be a targetable cell surface receptor. Specifically, antibodies binding to the carboxyl terminus of GRP78 induce tumor cell death by inhibiting the Akt pathway. Collectively, this knowledge underscores the importance of developing combination therapies that target both proliferating populations and nonproliferating drug-resistant tumor cell subpopulations. Moreover, this collective work identifies cell surface GRP78 as a promising therapeutic target on the cell surface of therapy-resistant tumor cells.