Potential to Eradicate Cancer Stemness by Targeting Cell Surface GRP78

Abstract

Cancer stemness is proposed to be the main cause of metastasis and tumor relapse after conventional therapy due to the main properties of cancer stem cells. These include unlimited self-renewal, the low percentage in a cell population, asymmetric/symmetric cell division, and the hypothetical different nature for absorbing external substances. As the mechanism of how cancer stemness is maintained remains unknown, further investigation into the basic features of cancer stemness is required. Many articles demonstrated that glucose-regulated protein 78 (GRP78) plays a key role in cancer stemness, suggesting that this molecule is feasible for targeting cancer stem cells. This review summarizes the history of finding cancer stem cells, as well as the functions of GRP78 in cancer stemness, for discussing the possibility of targeting GRP78 to eradicate cancer stemness.

Keywords: GRP78; cancer stem cells; cancer stemness; cell cycle; cell division.

Figure 1

The Hierarchy model and the Stochastic model are the two main hypotheses addressing cancer stemness. Owing to a lack of research investigations referring to the Stochastic model (A), this hypothesis is facing the challenge of being combined with the Hierarchy model (B) [50]. However, another hypothesis overriding these two relies on the novel ideas or state-of-art experimental designs or platforms that can evaluate the Stochastic model, leading to the in-depth understanding of how these two current models explain all aspects of cancer stemness.

Figure 2

Both cancer stem cells and non-stem-like cancer cells are hypothesized to express cell surface GRP78, but the amounts of cell surface GRP78 and its interactome of these two types of cells are different. (A) Previously, Chen et al. designed a quantitative mass spectrometry platform to detect the interactome of cell surface GRP78 in head and neck cancer cells [7]. Given that GRP78 silencing has a regulatory influence on stemness-related markers [7], it is logical to hypothesize that cancer stem cells possess a more diverse GRP78 interactome than non-stem-like cancer cells; and that cancer cells expressing a higher amount of cell surface GRP78 may possess the highest hierarchical rank of cancer stemness. (B) Due to the higher proliferation rate of cancer cells, an increase in plasma membrane synthesis in the endoplasmic reticulum is required, resulting in the translocation of resident chaperone GRP78 to the cell surface. Under this circumstance, non-stem-like cancer cells may express a certain amount of cell surface GRP78 even if there are no plasma membrane-bound proteins that need to be chaperoned to the subcellular compartment of the plasma membrane. GRP78 is likely secreted afterwards.

Figure 3

Distinct small populations of symmetrically divided cancer cells expressing ultra-high levels of cell surface GRP78 were consistently observed in the flow cytometry-based cell division assay. In a previously published article by Chen et al. [7], a high throughput flow cytometry-based cell division assay was developed to characterize the profile of asymmetric/symmetric cell divisions in the heterogeneous cell populations of three head and neck cancer cell lines, OECM1 (A), FaDu (B), and BM2 (C). In the three cancer cell lines that went through symmetric cell division (Gate R3 of Figure 5B,D,F of reference [7]), distinct cell populations expressed ultra-high levels of cell surface GRP78 (the R5 gates) consistently above the levels of major csGRP78 positive populations. (D) The quantification of the R5 gates of the three head and neck cancer cell lines. The percentages of R5 gates are 1–9% of the total cell populations.