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.

Extracellular Microvesicles Modified with Arginine-Rich Peptides for Active Macropinocytosis Induction and Delivery of Therapeutic Molecules

“…In addition, modifying the MV surface membrane with functional peptides for controlling macropinocytosis induction is considered to help develop the MV-based intracellular delivery of therapeutic/diagnostic molecules. Macropinocytosis pathways are significantly enhanced by cancer-related receptors such as EGFR and CXCR4, and oncogenic K-Ras expression, for attaining the efficient cellular uptake of nutrition from outside the cells. − A pancreatic cancer model in vivo has previously demonstrated strongly decreased cancer progression following treatment with macropinocytosis inhibitor . These findings inspired the development of exosome-based in vivo delivery of nucleic acids into oncogenic K-Ras-expressing pancreatic tumors, which significantly reduced cancer proliferation .…”

“…Active macropinocytotic cellular uptake was recently noted by us to play crucial roles for secreted exosomes. ,, Macropinocytosis is a clathrin-independent and actin-dependent endocytosis pathway, including actin rearrangements, lamellipodia formations, plasma membrane ruffling, and engulfment of large fluid volumes (>1 μm in diameter) outside cells. − Macropinocytosis has been shown to be stimulated by the activation of specific receptors, such as the epidermal growth factor receptor (EGFR) and C–X–C chemokine receptor type 4 (CXCR4). The expression of oncogenic K-Ras protein has also been shown to influence macropinocytosis, causing malignant progression. − A previous study conducted by us has demonstrated a significantly increased cellular uptake of exosomes via EGFR (e.g., 27-fold increased uptake of exosomes by EGFR activation with 500 nM EGF ligand for 24 h) in human epidermoid carcinoma cells (A431) caused by macropinocytosis induction. Oncogenic K-Ras expression (K-Ras G12C allele) in human pancreatic adenocarcinoma cells (MIA PaCa-2) also demonstrated high efficacy for cellular exosome uptake .…”

“…While MVs have been known to participate in cell–cell communications as described above, the mechanisms of cellular MV uptake relative to exosomes remain largely unknown . While the size of MVs ranges between 100 nm and 1 μm, clathrin-dependent endocytosis induced by ligand–receptor activation demonstrates the cellular uptake of particles having a maximum diameter of ∼120 nm, ,− possibly limiting the size for cellular MV uptake. In contrast, the macropinocytosis pathway, which is associated with a large fluid volume engulfment (>1 μm in diameter) outside cells, is considered to affect the efficacy of the cellular MV uptake and MV-mediated cell–cell communications.…”