Environmental Determinants of Ferroptosis in Cancer

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1		Yasaman Setayeshpour	--	1433	2023-08-07 19:58:36	\|
2	format correction	Dean Liu	-7 word(s)	1426	2023-08-08 02:27:01	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers15153861

Many metastasizing cancer cells are vulnerable to a particular type of cell death known as ferroptosis, which is an iron-dependent form of cell death caused by accumulative oxidative stress. Interestingly, many intracellular and extracellular factors can influence ferroptosis and, therefore, dictate the efficiency and route of tumor metastasis.

ferroptosis cancer metastasis TME

1. Introduction

The tumor microenvironment (TME) is the cellular and chemical environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules, and the extracellular matrix with various chemical and physical parameters ^[1]. The TME is often altered by tumors and can directly influence how tumors grow and spread, as well as how they respond to treatments ^[1]. For example, tumors often outgrow their blood supply, leading to areas of low oxygen or hypoxia. Hypoxia can make tumor cells more resistant to therapies, particularly radiation therapy, which requires oxygen to produce reactive oxygen species and cause DNA damage ^[2]. Another example includes the accumulation of lactic acid, which leads to a lower pH (acidic) environment and can limit the effectiveness of some drugs and, hence, promote a more aggressive tumor phenotype ^[3]^[4]. In addition, the TME often has a high interstitial fluid pressure and a dense extracellular matrix, which can physically prevent drugs from reaching the tumor cells ^[1]. Yet another important feature of the TME is the metabolic competition between rapidly proliferating cancer cells and the immune cells, with the cancer cells often outcompeting immune cells for nutrients, thereby suppressing immune function and potentially reducing the efficacy of immunotherapies ^[1].

Due to these extracellular influences on top of bearing significant genomic instability and a high frequency of somatic mutations, tumor cells bearing certain mutations may have survival or proliferation advantages and become “selected” for while exposed to various TME stresses and become the dominant component of tumors. This phenomenon is known as “somatic evolution” ^[5]. During somatic evolution, the tumor microenvironmental stresses serve as an important factor in selecting cancer cells, such as hypoxia enriched sites selecting for tumor cells that lack p53 ^[6]^[7], and glucose deprived sites selecting for tumor cells that bear Kras mutations ^[8]. While oncogenic driver mutations in tumor cells are often assumed to confer growth advantages due to proliferation or reduced cell death, many genes noted in the somatic mutations and copy number alterations (CNAs) in, for example, breast cancer may offer survival only under stresses ^[9]. This was shown by the findings that activating transcription factor 4 (ATF4) amplification and a higher ATF4-driven gene expression program in a subset of breast cancer cells provides a survival advantage under hypoxia and lactic acidosis ^[10]. These influences of the TME can also promote the development of drug-resistant tumor cells ^[5] and, therefore, make the TME an important target in cancer therapy. Strategies to normalize the TME, such as improving tumor blood flow ^[11] or targeting immunosuppressive cells ^[12], are under active investigation and could potentially enhance the effectiveness of existing cancer therapies. More importantly, more is being discovered about the specific death-inducing stresses within the TME and how they can be subverted by the metastasizing tumor cells ^[13]^[14]^[15]. Understanding this can further facilitate investigation of potential therapeutic approaches.

2. Ferroptosis, an Iron-Dependent Form of Regulated Cell Death

As indicated, genomic instability and dysregulated cellular processes due to the high frequency of mutations are one of the main drivers of tumor growth within the TME ^[5]. Therefore, maintaining genomic stability and homeostasis of major cellular processes is crucial for preventing the transformation of healthy cells into cancer cells ^[5]^[16]. Normally, several checkpoints and defense systems are in place to repair and reverse any error or imbalance in key cellular processes; in the case of excessive and irreversible cellular damage, different types of programmed cell deaths can be activated to kill malfunctioning cells as an effective tumor suppression mechanism ^[16]^[17]. The best-recognized type of cell death is apoptosis, which is triggered by DNA damage and other stresses to remove damaged cells ^[17]. It is well established that defects in the process of apoptosis play an important role in the tumor formation and drug resistance of cancer cells ^[18]. Another important cellular process to maintain is a balanced level of reactive oxygen species (ROS), which are often a product of high efficiency energy generation using oxygen-driven respiration ^[19]^[20]. While ROS are byproducts of necessary cellular processes and essential for signaling functions ^[19], excessive levels can lead to a toxic overaccumulation of oxidized cellular components, such as lipid peroxides ^[20]. Thus, there is a need for cellular antioxidant defense systems to repair the resulting lipid peroxides. In the case of excessive, irreversible membrane damage and lipid peroxidation, a specific type of iron-dependent programmed cell death called ferroptosis occurs ^[21]^[22].

Ferroptosis is a recently recognized form of regulated cell death characterized by iron dependency, lipid peroxidation, mitochondria shrinkage, and membrane content condensation ^[21]. Ferroptosis was first defined by Dixon et al. (2012) when they were studying the cell death mechanisms by which the small molecule drug erastin kills RAS-mutated cancer cells ^[23]. It has now been more than a decade since this first publication on ferroptosis, and since then, there have been significant advances in understanding the processes and determinants of ferroptosis, especially at the cellular level ^[24]. Ferroptosis occurs when cellular ROS generation and resulting lipid peroxidation outweigh cellular neutralizing mechanisms, including various antioxidants and enzymatic activities removing lipid peroxidation. Some of the main producers of ROS are Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), which can generate ROS as a result of electron transfer to oxygen molecules ^[25]. This results in the accumulation of lipid peroxidation, which would trigger ferroptosis unless lipid peroxidation is neutralized by dedicated lipid repair enzymes and antioxidant generation ^[24].

Due to their altered metabolism and having to pass through various microenvironmental stressors in order to metastasize, cancer cells are especially susceptible to ferroptotic cell death ^[15]. Interestingly, however, despite being more vulnerable to ferroptosis, many factors can protect cancer cells from ferroptosis and therefore enable the progression of metastasis ^[15]. Understanding how these mechanisms work and investigating ways to dismantle ferroptosis resistance both at the cellular and extracellular level has the potential to be a powerful therapeutic approach for preventing or minimizing cancer metastasis.

3. Genetic Regulators and Protectors of Ferroptosis

Ferroptosis has garnered a significant amount of attention in cancer studies because many oncogenic mutations and cellular states, while conferring resistance to various therapeutics, strongly promote ferroptosis ^[14]. Therefore, triggering ferroptosis has been shown to eliminate these ferroptosis-sensitive cancer cells with significant and promising therapeutic potential; however, it is still difficult to predict which tumors are most sensitive and would respond best to ferroptosis-inducing therapeutics ^[14]. As a result, many functional genomic studies have been employed to identify the genetic determinants of ferroptosis. These studies have revealed the importance of genetic regulation of several processes, such as the mesenchymal state, iron metabolism, lipid reprogramming, and the trans-sulfation pathways in ferroptosis ^[14].

4. Microenvironmental Regulators and Protectors of Ferroptosis

As explained, many genetic determinants have been identified for ferroptosis, but less is known about the role of non-genetic factors, understanding of which is critical for utilizing ferroptosis as a therapeutic approach in cancer. Intriguingly, while there are several microenvironmental inducers of ferroptosis in the body, there seem to be just as many protectors against ferroptosis, especially during various key steps of the metastatic cascade of cancer cells ^[26]. More than 90% of all cancer-related deaths are caused by metastasis, which is the spreading of cancer cells from the primary tumor to other body sites ^[27]^[28]^[29]. Hence, understanding how to dismantle this process is critical for developing effective cancer treatments to improve clinical outcomes.

Metastasis is not an easy process; to establish metastatic tumors, tumor cells need to go through multiple stress-inducing steps ^[26]. The metastatic cascade initiates with the progressive growth of tumor cells, followed by the local invasion of surrounding tissues, which involves loss of cellular contact and detachment from the extracellular matrix. Then, tumor cells will spread to existing or newly generated blood or lymphatic vessels, where they need to survive long enough during vasculature to become trapped in the vascular walls of distant tissues in order to extravasate. Finally, if the microenvironment in these tissues allows, cancer cells will egress and survive to proliferate, colonize, and form a metastatic tumor in the target organs ^[26]^[30]^[31]. These stress-inducing steps make metastasizing cancer cells particularly susceptible to ferroptosis, yet tumor cells still metastasize due to several protective elements along the way, which indicates that effective metastasis may be enabled by various environmental determinants of ferroptosis. These determinants include cellular contact, the epithelial-mesenchymal transition, presence or absence of exogenous fatty acids and other biocomponents, such as amino acids, glucose, lactate, and even other types of neighboring cells, as well as oxygen or acidity levels of the tumor microenvironment.

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Yasaman Setayeshpour

Yunji Lee

Jen-Tsan Chi

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Update Date: 08 Aug 2023

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