Karen Vousden___Metabolism, Tumor Cells, and Reactive Oxygen Species

Different forms of ROS have different functions; confusion arises from varying responses to ROS due to the specific type of ROS.
ROS such as superoxide and hydroxy radicals can damage cells, potentially leading to cell death.
Hydrogen peroxide can act as a signaling molecule, influencing post-translational modifications (oxidation of cysteines) and affecting protein function.
Reversible oxidation, similar to protein phosphorylation, can regulate proliferation, survival, angiogenesis, and migration in cells.
Cells have developed antioxidant defense mechanisms to cope with increased ROS, and cancer cells utilize these mechanisms for survival.
Many antioxidant defense systems depend on the reducing power of NADPH; systems generating NADPH are crucial for antioxidant defense.

The pentose phosphate pathway is a well-known source of NADPH.
ALDH1L2: A mitochondrial protein involved in the mitochondrial formate cycle, which burns one-carbon units to produce $CO_2$ and NADPH, participating in antioxidant defense within mitochondria.

ALDH1L2 expression is high in the pancreas, specifically in acinar cells, but not in ductal cells (cells of origin for pancreatic tumors).
Loss of ALDH1L2 in knockout mice leads to increased oxidative stress and lipid peroxidation in the pancreas.
In a cerulein-induced pancreatic damage model, ALDH1L2 knockout mice showed persistent acinar-to-ductal metaplasia (ADM) and impaired recovery of the acinar phenotype.
During pancreatic cancer development, ADM is crucial; KRAS mutations prevent ADM recovery, leading to pancreatic ductal adenocarcinoma.
PDAC tumors show reduced ALDH1L2 expression compared to normal pancreas.
Loss of ALDH1L2 accelerates ADM in early PDAC models, increasing metastasis without affecting overall survival in mice.

ALDH1L2 is expressed in other tumor types, including breast cancer, where its expression varies.
Depletion of ALDH1L2 in breast cancer cells (e.g., 468 cells) leads to a more invasive and migratory phenotype.
Overexpression of ALDH1L2 in syngeneic tumor lines limited metastasis in mouse models.
There is often reduced ALDH1L2 expression in metastases compared to primary tumors in human breast cancer.

ALDH1L2 influences the one-carbon cycle; its activity limits other uses of THF, including nucleotide synthesis.
Knockdown of ALDH1L2 increases formate and formyl-methionine production, leading to increased mitochondrial protein synthesis and formylated peptides.
Formylated peptides, similar to those produced by bacteria, can bind to formyl peptide receptors on immune cells, activating them.
Tumor cell lines also express formyl peptide receptors; stimulation of these receptors promotes tumor cell migration.
Increased formate levels are observed in the tumor microenvironment of PDAC, which may attract immune cells.
Formate levels in plasma could potentially serve as an early detection marker for tumor development.

Regulation of Formate: Loss of alpha h one l two leads to increased formate and formyl peptide receptor signaling.
Increased ROS: As previously noted, ROS can also signal to drive invasion and metastasis.
Tumor Microenvironment: High levels of formate in the tumor microenvironment may attract immune cells.