The impact of calcium signaling on tumor progression has been explored in several studies (Marchi and Pinton, 2016; Bong and Monteith, 2018). Calcium promotes the development of malignant behaviors by regulating cellular activities such as proliferation, migration, and apoptosis resistance (Morciano et al., 2018). This effect might be caused by dysregulation of pumps and channels and the resulting unequal calcium concentrations (Makena and Rao, 2020). Interestingly, several molecules associated with calcium exchange, including SOCE and calcium permeable transient receptor potential (TRP) channels, have been linked to cancer progression and metastasis (Chen et al., 2013; Yang et al., 2013).

Recently STIM1 and Orai1 have been shown to be upregulated in thyroid cancer patient tissue samples as well as in thyroid cancer cell lines compared with primary thyroid cells (Asghar et al., 2021). In addition, clinically, STIM1 has been found to be overexpressed in breast cancer, (Yang et al., 2017), colorectal cancer, (Wang et al., 2015), and lung cancer, (Zhan et al., 2015), and is associated with factors indicating poor prognosis, such as increased tumor size. Moreover, Orai1 has also been found to be overexpressed in esophageal cancer (Zhu et al., 2014; Wang et al., 2017). Then, SOCE chemical inhibitors and siRNAs targeting Orai1 and 2 have been found to inhibit calcium uptake and inhibit cell proliferation and migration (Singh et al., 2020). The SOCE is decreaed in STIM1 knockdown and Orai1 knockdown thyroid cancer cells. This resulted in decrease in thyroid cancer cells proliferation. In xenograft zebrafish model, the STIM1 knockdown decreased human thyroid tumor growth and also activated apoptosis (Asghar et al., 2021).

In conclusion, when E-Syt1 and E-Syt2/3 form heterodimers in cancer cells, these heterodimers can activate the SOCE pathway and lead to massive calcium influx. Dysregulated calcium signaling plays an important role in the uncontrolled growth and development of tumors (Tremblay and Moss, 2016). In contrast, knockdown of E-Syt1 or E-Syt2 affect the localization and aggregation of STIM1, thereby affecting the activation of the SOCE pathway (Woo et al., 2020). Figure 1 shows the involvement of SOCE in regulating calcium signaling in various tumor progression.

There are two pathways of glucose metabolism: mitochondrial oxidative phosphorylation and glycolysis. Glycolysis is inhibited in normal mammalian cells under aerobic conditions. However, tumor cells have the ability to switch between the two energy metabolism pathways, a phenomenon called the Warburg effect (Liberti and Locasale, 2016). Even in oxygen-rich conditions, glycolysis is activated in tumor cells, converting glucose into lactic acid to produce ATP, and this state is characterized by rapid proliferation and resistance to cell death. Glycolysis has long been considered a major metabolic process of energy production and anabolic growth in cancer cells (Porporato et al., 2018). Calcium plays an important role in this metabolic transition (Bondarenko et al., 2014; Bittremieux et al., 2016). Plasma membrane Ca2+ ATPase (PMCA) is closely involved in intracellular calcium concentration control. It reduces the calcium concentration in the cytoplasm not only by direct efflux but also by controlling inositol-1,4,5-triphosphate (IP3R) formation and reducing calcium release from the endoplasmic reticulum (Padányi et al., 2016). However, E-Syt senses a decrease in intracellular or endoplasmic reticulum calcium ion concentration in MCSs, which in turn anchors with PI (Porter and Palade, 1957; Okeke et al., 2016) P2. (Cortés et al., 2019; Dietz et al., 2022). The local concentration of PI (Porter and Palade, 1957; Okeke et al., 2016) P2 increases, and after decomposition, more IP3 is generated (Ehrlich et al., 2011; Chang and Liou, 2016). IP3 binds to receptors (IP3R) on the endoplasmic reticulum and initiates the release of calcium ions. In addition, an increase in local concentration of PI (Porter and Palade, 1957; Okeke et al., 2016) P2 can also activate the SOCE pathway and promote extracellular calcium influx (Chen YJ. et al., 2017). In other words, E-Syt, MCSs, SOCE and PMCA jointly regulate the intracellular calcium concentration. High calcium concentration further regulates the Warburg effect in tumor cells, resulting in proliferation and resistance to death (Riera Leal et al., 2020). This process is explained in Figure 3.

In recent years, cisplatin has been widely used as an anticancer drug in clinical practice that exerts effects by inhibiting the activity of key enzymes in the glycolysis pathway in tumor cells. However, overcoming cisplatin toxicity and resistance has historically been a challenge in tumor therapy. Due to the Warburg effect in tumor cells, Wang et al. (2019) designed some new platinum compounds and synthesized a triphenylphosphonium-modified terpyridine platinum (II) complex (TTP). By inhibiting thioredoxin reductase (TrxR) in mitochondria and the cytoplasm, TTP damages mitochondrial morphology and function and simultaneously inhibits mitochondrial oxidative phosphorylation and glycolysis, thus reducing the overall metabolic level in tumor cells. Finally, it can inhibit the proliferation of tumor cells and overcome cellular drug resistance.

Lipids, because of their hydrophobicity, are the physical basis of all living organisms (Nicolson, 2014). Lipids play a crucial role in cell proliferation. As cells proliferate, resynthesized lipids provide phospholipid components for proliferation and are used to form new mitotic membranes and organelle membranes. They also play important roles as signaling molecules in a variety of cellular activities (Cruz et al., 2019). However, due to the reprogramming of lipid metabolism, the newly formed membrane structures have different degrees of curvature and fluidity (Zhang et al., 2020). In normal cells, E-Syt proteins help to ensure lipid homeostasis between cell membranes and lipid vesicles. They may maintain lipid homeostasis through interactions of lipids with different cell membranes. Studies have confirmed that knockdown of E-Syt proteins can affect lipid transport functions, especially cellular processes related to lipid transport and lipid homeostasis (Saheki et al., 2016). However, studies have shown that some tumor cells may express high levels of E-Syts, leading to uneven or abnormal lipid distribution (Sun et al., 2009; Saheki et al., 2016). The main impacts of lipid structure are as follows.

First, lipid structure affects the curvature and tension of the tumor cell membrane. Phospholipids, such as phosphatidylcholine (PC), have a cylindrical shape dictated by the head-to-tail ratio and spontaneously form a bilayer in water (van Meer and de Kroon, 2011). Phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylserine (PS), and cholesterol (CL) are considered conical lipids because they have small heads and distorted membranes with negative curvature (Nicolson and Ash, 2014). However, lysophosphatidylcholine (LPC) has a large head-to-tail ratio, forming an inverted conical shape and resulting in positive curvature of the membrane. These lipids affect the curvature and tension of the membrane, lowering the energy needed for fusion and vesicle transport (Frohman, 2015). In addition, differences in membrane curvature and tension are involved in the processes of endocytosis/exocytosis, cell division and cell motility, which are closely related to tumor migration and invasion (Tsujita et al., 2021). For example, malignant cells have lower plasma membrane tension than normal cells, helping tumor cells offset their positive membrane curvature to facilitate their migration and invasion (Simunovic et al., 2019; Yesylevskyy et al., 2019).

The other factor is membrane fluidity. Lipid saturation is related to fluidity. Saturated lipids are beneficial for the orderly synthesis of membranes. Unsaturated lipids reduce this lipid accumulation and increase membrane fluidity (Nicolson and Ash, 2014). Dysregulation of membrane lipids results in higher or lower levels of membrane lipids in cancer cells than in normal cells, resulting in changes in membrane fluidity (Peetla et al., 2013). Cells with a low membrane lipid content have membranes that are more easily deformed and enter blood vessels more easily (Hendrich and Michalak, 2003). In addition, membrane lipids play an important role in multidrug resistance (MDR). Cancer cells have been shown to acquire MDR when the lipid components of their membranes are altered (Hendrich and Michalak, 2003). In multidrug-resistant cells, the membrane lipid content is higher, the membrane is less fluid, and the membrane permeability is lower than in normal cells, which leads to poor permeability of chemotherapy drugs in these cells (Niero et al., 2014). It has been reported that the development of nanostructured lipid carriers can overcome MDR during breast cancer (Li et al., 2018) and metastatic colon cancer (Karthika and Sureshkumar, 2019) treatment.

In summary, lipids transported through the SMP bridges of E-Syt can affect the curvature, tension, and fluidity of the membrane. Different membrane curvature and tension are involved in the processes of endocytosis/exocytosis, cell division, and cell motility, which are closely related to tumor migration and invasion (Tsujita et al., 2021). Moreover, lipid metabolic reprogramming is directly involved in the malignant transformation and progression of cells (Preta, 2020). Therefore, changes in membrane tension, fluidity and permeability in tumor cells affect the entry of chemotherapy drugs into these cells, resulting in drug resistance (Chabanel et al., 1985). Additionally, identifying the changes in lipids in the new membranes of these cells is anticipated to be greatly beneficial for the early diagnosis of cancer. Numerous human organs have been included in recent studies on the use of lipidomics in the diagnosis of cancers, including lung, (Ros-Mazurczyk et al., 2017), breast, (Corona et al., 2021), colon, (Sánchez-Martínez et al., 2015), gastric, (Wei et al., 2021), endometrial, (Seth et al., 2012), pancreatic, (Bai et al., 2021), ovarian, (Ji et al., 2020), liver, (Alannan et al., 2020), kidney (Van Hemelrijck et al., 2012) and even glial (Garanti et al., 2016) tumors. In addition, studies have shown that knockdown methods and conditions may also have an impact on lipid alterations (Woo et al., 2020). Studying the effects of E-Syt protein knockdown is crucial for obtaining a deeper understanding of the mechanisms of lipid transport, lipid homeostasis, and cell membrane function, especially in lipid-related diseases (Woo et al., 2020).

In addition, cancer cells require large amounts of ATP to proliferate uncontrollably and invade surrounding tissues, thereby degrading the extracellular matrix (ECM) and migrating along ECM fibers (Snaebjornsson et al., 2020).

First, when lipid synthesis increases to a certain level in normal cells, lipids bind to the endoplasmic reticulum transmembrane protein INSIG, which blocks the processing of SREBP, a key transcription factor for lipid synthesis. This prevents SREBP from entering the nucleus for transcription, thus inhibiting lipid synthesis (Shao and Espenshade, 2014).

In cancer cells, however, this negative feedback system is inhibited, providing tumor cells with a steady supply of lipids (Lewis et al., 2015). Guo et al. (2019) knocked down SCAP, which inhibited the growth and adipogenic differentiation of liver cancer cells. Additionally, in prostate cancer, SREBP-2 induces the proliferation, invasion and migration of prostate cancer cells. Overexpression of SREBP-2 increases the number of prostate cancer stem cells. Genetic silencing of SREBP-2 inhibits the proliferation and metastasis of prostate cancer cells (Li et al., 2016). Through this INSIG-SREBP-SCAP pathway in MCSs, endogenous lipid synthesis is increased in tumor cells.

Second, mammalian cells can also obtain cholesterol by taking up low-density lipoprotein (LDL). Low-density lipoprotein receptors (LDLRs) are carried to the lysosome, where they are degraded by lysosomal acid lipase (LAL), resulting in the release of free cholesterol, which promotes cancer cell development. There are many adipose cells in breast cancer tissue. Coculture with cancer cells can activate lipolysis in adipose cells and release fatty acids into the extracellular space (Zhang et al., 2019). Subsequent studies have revealed that these fatty acids are in turn taken up by cancer cells, resulting in increased proliferation and migration of cancer cells (Rinninger et al., 2014).

For cancer cells, metastasis is difficult. Tumor cells must be detached from the primary tumor and enter blood vessels. This is a process that kills most circulating tumor cells (CTCs) (Lianidou et al., 2014). Eventually, CTCs may extravasate and find a suitable site for growth in a different tissue, where they may become resistant to most treatments until metastatic disease develops. It has been reported that lipids play an important role in this process of tumor metastasis, and this role may be related to membrane lipid saturation and transporters, but the related mechanisms still need to be elucidated in future studies. There was a study eliminated that the expression of lipid transporters were close to predict the survival rate of breast cancer (Zalba and Ten Hagen, 2017).

Jirasek et al. (2016) found a link between the aggressiveness of prostate cancer and a compound produced by cholesterol metabolism in cells. They later extended their findings to pancreatic cancer and showed that drugs used to treat atherosclerosis may have therapeutic promise in pancreatic and other cancers. The researchers found accumulation of cholesterol esters in human pancreatic cancer samples, suggesting a possible link between cholesterol esterification and metastasis (Jirasek et al., 2016). The presence of excess cholesterol results in the cholesterol storage in lipid droplets within cancer cells in the form of cholesterol esters. Inhibition of cholesterol ester formation may be a new strategy for the treatment of metastatic pancreatic cancer.

Lipids in urinary exosomes can be used as markers for prostate cancer. Recently, Skotland et al. (2017) studied the potential of lipids in urinary exosomes as biomarkers for prostate cancer. A total of 107 lipids were quantified in urinary exosomes. Several differences in lipids were discovered between urinary exosomes and exosomes derived from cell lines. The findings highlighted the importance of lipids in exosomes for biomarker research in vivo (Beloribi et al., 2012).