Targeting Phospholipid Metabolism in Cancer

Abstract

All cancers tested so far display abnormal choline and ethanolamine phospholipid metabolism, which has been detected with numerous magnetic resonance spectroscopy (MRS) approaches in cells, animal models of cancer, as well as the tumors of cancer patients. Since the discovery of this metabolic hallmark of cancer, many studies have been performed to elucidate the molecular origins of deregulated choline metabolism, to identify targets for cancer treatment, and to develop MRS approaches that detect choline and ethanolamine compounds for clinical use in diagnosis and treatment monitoring. Several enzymes in choline, and recently also ethanolamine, phospholipid metabolism have been identified, and their evaluation has shown that they are involved in carcinogenesis and tumor progression. Several already established enzymes as well as a number of emerging enzymes in phospholipid metabolism can be used as treatment targets for anticancer therapy, either alone or in combination with other chemotherapeutic approaches. This review summarizes the current knowledge of established and relatively novel targets in phospholipid metabolism of cancer, covering choline kinase α, phosphatidylcholine-specific phospholipase D1, phosphatidylcholine-specific phospholipase C, sphingomyelinases, choline transporters, glycerophosphodiesterases, phosphatidylethanolamine N-methyltransferase, and ethanolamine kinase. These enzymes are discussed in terms of their roles in oncogenic transformation, tumor progression, and crucial cancer cell properties such as fast proliferation, migration, and invasion. Their potential as treatment targets are evaluated based on the current literature.

Inherently decoupled1H antennas and31P loops for metabolic imaging of liver metastasis at 7 T

“…Unfortunately, response to treatment varies greatly between patients, even when suffering from the same primary tumor . New tools to predict or measure treatment response before or shortly after the start of treatment are urgently needed to prevent the long‐term exposure of patients to ineffective treatments …”

“…In the preclinical setting, 31 P spectroscopy is already a key tool for elucidating cancer metabolism and quantitative evaluation of new treatments . As such, clinical 31 P spectroscopy is of great interest as a potential tool for tracking treatment response . Phosphorus spectroscopy provides a multitude of information on cancer metabolism and the local environment, such as phospholipid metabolism (phosphoethanolamine [PE], phosphocholine [PC], glycerophosphoethanolamine [GPE] and glycerophosphocholine [GPC]), cellular energetics and intracellular and extracellular pH (via inorganic phosphate [Pi]) .…”

Chemical fixation to arrest phospholipid signaling for chemical cytometry

“…Phospholipids are crucial components in all living cells, serving as second messengers for signal transduction and as structural components for cell membranes [1,2]. Several lipid metabolic pathways exist in cells regulating cellular biology, although measuring the ebb and flow of information within these pathways has proven a challenge due to difficulties in analyzing lipid metabolites in single cells.…”

“…One example is the G-protein coupled phospholipase C (PLC) pathway which serves a critical role in production of the lipid second messengers diacylglycerol (DAG) and inositol trisphosphate (IP 3 ) by metabolism of phosphatidylinositide (4,5)-bisphosphate (PI[4,5]P 2 ) [3,4]. This pathway acts to regulate multiple cellular functions, such as proliferation, mitogenic signal transduction, and response to external stimuli via its influence on downsteam effectors, such as protein kinase C and intracellular calcium [1,5,6]. Moreover, multiple other metabolites upstream and downstream of PI(4,5)P 2 are known to be of importance in cellular function, but studies have been limited by a lack of appropriate technologies to make measurements in individual cells.…”

Trichoblastic Fibroma of the Skin Mimicking Primary or Secondary Breast Cancer

“…The aberrant choline metabolism is established as universal metabolic indicator of cancer. However, MRS of the breast is a diagnostic modality still in progress, indicating that quantification of choline compounds may lead to increased reliability in differentiation of breast tumors [27][28][29].…”