Atypical Macropinocytosis Contributes to Malignant Progression: A Review of Recent Evidence in Endometrioid Endometrial Cancer Cells

Abstract

Macropinocytosis is an essential mechanism for the non-specific uptake of extracellular fluids and solutes. In recent years, additional functions have been identified in macropinocytosis, such as the intracellular introduction pathway of drugs, bacterial and viral infection pathways, and nutritional supplement pathway of cancer cells. However, little is known about the changes in cell function after macropinocytosis. Recently, it has been reported that macropinocytosis is essential for endometrial cancer cells to initiate malignant progression in a dormant state. Macropinocytosis is formed by a temporary split of adjacent bicellular junctions of epithelial sheets, rather than from the apical surface or basal membrane, as a result of the transient reduction of tight junction homeostasis. This novel type of macropinocytosis has been suggested to be associated with the malignant pathology of endometriosis and endometrioid endometrial carcinoma. This review outlines the induction of malignant progression of endometrial cancer cells by macropinocytosis based on a new mechanism and the potential preventive mechanism of its malignant progression.

Keywords: LSR; dormancy; endometrioid-endometrial carcinoma; endometriosis; macropinocytosis; tight junctions.

Figure 1

Overview of the endocytic pathways. Phagocytosis incorporates extracellular components through phagocytic receptors. Cells that phagocytose with high efficiency are termed professional cells, whereas those with low efficiency are termed non-professional cells. Pinocytosis nonspecifically incorporates soluble components, such as proteins and growth factors. Small vesicles are formed through clathrin- and caveolae-mediated pathways during pinocytosis. The pathway of extensive incorporation, with membrane protrusion from the cell surface, is termed macropinocytosis. The endometrial cancer cell Sawano exhibits macropinocytosis caused by a transient split of intercellular spaces.

Figure 2

Schematic diagram of the LSR ligand-induced transient macropinocytosis derived from intercellular split. (Upper panels) In mature epithelial cells, LSR accumulates in apical tricellular junctions. Administration of the LSR ligand splits the adjacent intercellular spaces, leading to macropinocytosis. The intercellular adhesion apparatus was not disrupted by macropinocytosis. G, intercellular gap; TJ, tight junctions; AJ, adherens junctions; D, desmosomes; N, nucleus; Mt, mitochondria. Bar, 1 μm. (Lower panels) The gap between adjacent cells expanded and filled with extracellular fluid, one hour after administration of the LSR ligand. Two hours after addition, numerous macropinosomes that incorporated the extracellular fluid appeared in the cytosol. The vesicles disappeared three hours after addition. The cells then initiated malignant cell growth, resulting in multilayered cell growth. This pathway was suppressed in the presence of a macropinocytosis inhibitor.

Figure 3

Schematic representation of the mechanism by which endometrial cancer Sawano initiates malignant cell growth. Mature epithelial sheets, where LSR localize at tricellular tight junctions, suppress macropinocytosis. LSR ligand administration leads to the translocation of LSR from tricellular tight junctions. LSR interacts with Rab5 in the bicellular region, resulting in decreased LSR expression. SLC9A1 is presumably activated through a signal that accompanies the alteration of LSR localization, followed by Rac activation. SLC9A1 scaffolds Raf and ERK downstream of KRAS. Activated Rac induces JNK activation, resulting in the formation of macropinocytosis, followed by an increase in planar cell migration, and eventually, multilayered cell growth.