Cell membrane modulation as adjuvant in cancer therapy

Abstract

Cancer is a complex disease involving numerous biological processes, which can exist in parallel, can be complementary, or are engaged when needed and as such can replace each other. This redundancy in possibilities cancer cells have, are fundamental to failure of therapy. However, intrinsic features of tumor cells and tumors as a whole provide also opportunities for therapy. Here we discuss the unique and specific makeup and arrangement of cell membranes of tumor cells and how these may help treatment. Interestingly, knowledge on cell membranes and associated structures is present already for decades, while application of membrane modification and manipulation as part of cancer therapy is lagging. Recent developments of scientific tools concerning lipids and lipid metabolism, opened new and previously unknown aspects of tumor cells and indicate possible differences in lipid composition and membrane function of tumor cells compared to healthy cells. This field, coined Lipidomics, demonstrates the importance of lipid components in cell membrane in several illnesses. Important alterations in cancer, and specially in resistant cancer cells compared to normal cells, opened the door to new therapeutic strategies. Moreover, the ability to modulate membrane components and/or properties has become a reality. Here, developments in cancer-related Lipidomics and strategies to interfere specifically with cancer cell membranes and how these affect cancer treatment are discussed. We hypothesize that combination of lipid or membrane targeted strategies with available care to improve chemotherapy, radiotherapy and immunotherapy will bring the much needed change in treatment in the years to come.

Keywords: Cancer adjuvant; Cell membrane; Lipid modulation; Lipidomics.

Figure 1

Schematic representation of a cellular membrane depicting a selection of phospholipids as they appear in a bilayer. The liquid-ordered phase (Lo) typically harbors saturated phospholipids and cholesterol and therefore has a relatively rigid nature with a higher density of packing. The liquid-disordered phase is reached at temperatures above the transit temperature (Tm), which is typified by a more loose packing and less rigid nature.

Figure 2

Shape and structure of Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and lyso-phosphatidylcholine (LPC). As is depicted, the makeup of these lipids determine to great extend the geometry of the structures in which they participate.

Figure 3

Different stages of lipid bilayers depending on the composition and ambient temperature. When heating up the membrane changes from a rigid Gel state (So) to a more fluid and less dense Liquid state (Ld) when going through the transition temperature (Tm). Addition of cholesterol stabilizes the effect of temperature by providing denser packing and an increased rigidity. Presence of unsaturated phospholipids results in impaired packing and a higher state of fluidity. The double bounds in these lipids results in bends in the fatty chains causing repulsing and steric hindrance between the lipids.

Figure 4

Schematics of two types of lipid rafts or lipid domains. A) Cholesterol enriched lipid raft with EGFR embedded and part of the downstream cascade. B) Ceramide enriched domain with the Fas receptor embedded and the downstream apoptosis process flow chart. Epidermal growth factor (EGF), sphingomyelin (SM), phosphatidylcholine (PC), cholesterol (Chol), phosphatidylserine (PS) and Fas-Associated protein with Death Domain (FADD).

Figure 5

A: Structural depiction of short and long chain ceramides within a membrane. Sphingolipids (SL), cholesterol (Ch), phosphatidylcholine (PC). B: Molecular structures of ceramide, sphingomyelin and three examples of short chain ceramides. The short chain ceramides can be identified by a truncated chain which is significantly shorter compared to other.

Figure 6

Schematic representation of the Ceramide/Sphingomyeline cycle and main strategies to modulate it in cancer therapy. Sphingomyelin conversion can be modulated resulting in elevated levels of ceramides which favor apoptosis, while levels of ceramide can be maintained by inhibition of its processing to sphingomyelin.