Rafting Down the Metastatic Cascade: The Role of Lipid Rafts in Cancer Metastasis, Cell Death, and Clinical Outcomes

Abstract

Lipid rafts are tightly packed, cholesterol-and sphingolipid-enriched microdomains within the plasma membrane that play important roles in many pathophysiological processes. Rafts have been strongly implicated as master regulators of signal transduction in cancer, where raft compartmentalization can promote transmembrane receptor oligomerization, shield proteins from enzymatic degradation, and act as scaffolds to enhance intracellular signaling cascades. Cancer cells have been found to exploit these mechanisms to initiate oncogenic signaling and promote tumor progression. This review highlights the roles of lipid rafts within the metastatic cascade, specifically within tumor angiogenesis, cell adhesion, migration, EMT, and transendothelial migration. Additionally, the interplay between lipid rafts and different modes of cancer cell death, including necrosis, apoptosis, and anoikis will be described. The clinical role of lipid raft-specific proteins caveolin and flotillin in assessing patient prognosis and evaluating metastatic potential of various cancers will be presented. Collectively, elucidation of the complex roles of lipid rafts and raft components within the metastatic cascade may be instrumental for therapeutic discovery to curb pro-metastatic processes. Research.

Regulation of Death Receptor Signaling by S-Palmitoylation and Detergent-Resistant Membrane Micro Domains—Greasing the Gears of Extrinsic Cell Death Induction, Survival, and Inflammation

“…Among the hallmarks of cancer is the ability for sustained angiogenesis, invasion, and metastasis, which are highly associated with altered lipid composition and membrane fluidity of cancer cells. Approaches to targeting lipid rafts in cancer cells have been summarized in various comprehensive reviews [ 217 , 218 , 219 ].…”

Oxaliplatin Resistance in Colorectal Cancer Enhances TRAIL Sensitivity Via Death Receptor 4 Upregulation and Lipid Raft Localization

“…While sufficient DR4 expression is important for sustained apoptotic signaling, DR4 localization and compartmentalization within lipid rafts is unequivocally vital. Lipid rafts enhance the signaling capacity of surface receptors through a multitude of mechanisms (15). For example, LRs promote death receptor trimerization which is needed for signal transduction, act as concentrating platforms for DISC assembly and the recruitment of death domains, and protect DRs from internalization or enzymatic degradation (14).…”

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

“…Unwittingly, these advances have highlighted previously unappreciated complexities of interactions between lipid and protein components of lipid rafts. Thus, an intensive 10 years of study has led to the discovery that well known proteins involved in migration, cell adhesion, invasion, angiogenesis and metastasis are localized in lipid rafts ( Figure 1 ) [ 89 ].…”

“…They include cell adhesion, migration and epithelial-to-mesenchimal transition (EMT), which is characterized by the loss of contact between cells and acquisition of fibroblastic phenotype. There are recent reviews on the role of lipid rafts in metastasis and EMT [ 89 , 90 ]. For example, disrupting lipid rafts with cyclodestrin or nystatin reverses EMT induced by TGF-β1 in breast cancer and gastric cancer cells, respectively [ 100 , 101 ].…”

“…Unwittingly, these advances have highlighted previously unappreciated complexities of interactions between lipid and protein components of lipid rafts. Thus, an intensive 10 years of study has led to the discovery that well known proteins involved in migration, cell adhesion, invasion, angiogenesis and metastasis are localized in lipid rafts (Figure 1) [89]. through activation of PI3K/AKT or MAPK pathways lead to survival and proliferation; dead receptors (DR) such as TRAIL and Fas activate caspase 8 and the apoptotic cascade; the chemokine receptor CXCR4 activation leads to migration; the transforming growth factor-1 β receptor (TGFR) is involved in epithelial to mesenchimal transition (EMT).…”