A Review of Notch Signaling in Non-Small Cell Lung Cancer (NSCLC)
Currently, there are several approaches to treatment for small cell lung cancer. One of them involves the use of radiation therapy. Another is the use of drugs called chemotherapeutic agents. There are also other forms of treatment, such as immunotherapy.
Smoking
Among all cancers, lung cancer is the most common and it accounts for approximately one of eight new cancers diagnosed worldwide each year. Its prevalence has been increasing in recent years.
Lung cancer is often caused by tobacco use. Various chemicals found in tobacco smoke damage the DNA in the cells of the lungs, which can lead to tumor formation.
There are several histologic types of lung cancer, primarily adenocarcinoma, and squamous cell carcinoma. Most people who have this type of cancer have smoked.
The American Cancer Society estimates that smoking causes 90% of lung cancer in men and women. However, there are a number of other factors that may influence the risk. Occupational exposures are a major risk factor, as are a family history of cancer and previous lung disease. Several studies have focused on the role of smoking in lung cancer, but only a few have explored the effects of specific cell types.
Smoking causes a variety of adverse health effects, including airflow limitation and increased oxidative stress. It also increases the risk of developing other health conditions, such as lung cancer. Depending on the amount of cigarettes smoked, the risk of lung cancer increases.
Tobacco products are known to contain at least 70 chemicals. Thousands of these are thought to cause cancer. Lung cancer can occur even in smokers who have not smoked for a long time.
The best-known and most commonly used method of reducing the risk of lung cancer is to stop smoking. But quitting isn’t always easy.
Notch receptor protein
During the course of development, Notch signaling plays a critical role in tissue repair, cell fate choice, and cell specification. It has been a target for a number of cancer therapeutic strategies. This review discusses Notch’s involvement in non-small cell lung cancer (NSCLC), and its relevance in therapeutic perspectives for NSCLC.
Notch signaling involves a series of protein interaction events. Its receptors are found on the plasma membrane. These receptors interact with Serrate-like proteins. A protein called ADAM-17 is a key regulator of Notch. This metalloprotease catalyzes the cleavage of the extracellular domain of the Notch receptor to facilitate the endocytosis of the NECD-ligand complex. Afterward, g-secretase-mediated cleavages at the S3 and S4 sites occur, releasing the Notch b fragment into the extracellular space.
Notch is a critical component of the proximodistal axis, which is responsible for maintaining the fundamental balance between the epithelial and neuroepithelial components of the lung. Notch-1 activity suppresses ciliated cell fate choice and directs differentiation of the epithelial component of the lung. Notch signaling has also been shown to promote the survival of cancer cells in the hypoxic regions of NSCLC.
HH signaling
HH signaling is one of the most important tumor-promoting pathways and has been linked to many cancer types. The pathway is involved in tumor progression, metastasis, and EMT. It can be activated in a variety of ways, including autocrine, classical, non-classical, and mutational. The downstream effects of Hh activation are proliferation, telomeric activity, and differentiation.
In several types of cancer, aberrations of the Hh pathway have been implicated. These are often associated with alterations in the GLI transcription factors, which are the most likely targets for inhibitors.
The transcription of these proteins is regulated by several important oncogenic pathways. Among these, the pathways that directly activate these proteins are PI3K and AKT. These two pathways have been shown to be essential for cancer development and progression.
In addition to modulating the tumor cell’s metabolism and promoting EMT, Hh signaling has been found to influence the tumor cell’s cellular and extracellular matrix remodeling. It also has been shown to activate the expression of genes involved in proliferation and cellular transformation. It has also been shown to promote angiogenic activity.
The pathway is characterized by a complex network of molecules. It involves several transcription factors, such as BRD4, and BET. These proteins are epigenetically regulated and play a crucial role in the transcriptional output of Hh.
The signaling cascade is activated through the presence of Hh ligands and PTCH receptors. The binding of Hh ligands to PTCH receptors results in the translocation of the transcription factors to the nucleus.
Immune infiltration
Several studies have shown that pre-invasive NSCLC lesions may be the sites of active immune escape mechanisms. These immune escape mechanisms are associated with intratumor heterogeneity and promote disease progression to metastatic disease. Moreover, they contribute to resistance to immune checkpoint blockade (ICB) therapy. In this regard, the present study investigated the relationship between tumor mutational burden, PD-L1 expression, and immune cell infiltration in human SCLC.
The increased presence of immune cells in the tumor nest was associated with high tumor mutational burden and inflammatory T-cell-mediated responses. This effect was associated with higher CD8-positive T-cell infiltration and the upregulation of antigen-processing pathways. It was also accompanied by a favorable transcriptomic profile. It was also associated with a lower PD-L1 biomarker staining.
The NE-high primary tumors displayed higher tumor MHC II expression. They also exhibited a higher proportion of plasmacytoid dendritic cells and M1 macrophages. In the LN metastases, the intratumoral expression of IDO was higher. It was correlated with the expression of PVR in primary tumors. This correlation was significant at the 0.01 level (two-tailed Spearman test).
The high TMB of lung squamous carcinoma tumors was associated with increased immune cell infiltration, chemokine signaling pathways, and a favorable transcriptomic profile. Moreover, it was accompanied by a high proportion of Th1/Th2 T cells and a lower proportion of M2 macrophages.
Furthermore, the expression of PD-L1 and PD-1 was associated with the aggressive phenotype of human SCLC. This was also confirmed in an independent external cohort.
Oxidation-reduction (Re-dox) subtype
During the course of cancer development, cancer cells generate high levels of reactive oxygen species (ROS). In response to this excess, cancer cells increase their antioxidant defense system to neutralize these excess ROS. This is a crucial mechanism to combat tumor progression.
ROS are produced by the endoplasmic reticulum and mitochondria. They are toxic to normal cells. They also act as fuel for cancer cells. This fuel is generated when mitochondria are damaged. This damage is initiated by oxidative stress. When it is not controlled, ROS can cause cell death and lead to tumor development.
To identify the best method to suppress tumor growth, researchers reviewed the literature. They found that pharmacological inhibition of antioxidant defense systems may benefit cancer patients.
They also noted that a redox shift from an antioxidant to a prooxidant state may inhibit tumor development. However, preclinical studies evaluating redox modulators are conflicting. They need further research to determine the efficacy of this strategy.
A better understanding of the complex interplay between ROS and antioxidants in cancer progression may spur the development of natural modulators. Moreover, a better understanding of the role of these factors may also help develop more effective therapeutic strategies.
A good example of the redox effect is shown in the regulation of p65 DNA binding activity. This is one of the most important functions of the antioxidant defense system, which includes the peroxisomal proteins, CD44v9, and the Nrf2 gene.
Radiation therapy
Typically, patients with extensive-stage small cell lung cancer (ES-SCLC) are treated with platinum-based chemotherapy followed by prophylactic cranial irradiation. For limited-stage disease, local treatment with surgery is often considered. However, there are some exceptions. Currently, a randomized phase III trial compared cisplatin with irinotecan in ES-SCLC patients.
Despite this, small-cell lung cancer has a poor survival rate. Nevertheless, a study has shown that thoracic radiotherapy may be beneficial in improving the overall survival of patients with extensive-stage small-cell lung cancer.
The results of this study suggest that thoracic radiotherapy should be offered as a second-line treatment for patients with ES-SCLC who respond to chemotherapy. In addition, thoracic radiotherapy is associated with reduced rates of intrathoracic recurrence and a lower risk of progression compared with the control group. In a multivariate analysis, thoracic radiotherapy was shown to improve the median overall survival by about four months.
The thoracic radiotherapy group had a higher survival rate at six months and two years, as well as a lower risk of progression than the control group. The difference was not statistically significant. At one year, the thoracic radiotherapy group had fewer locoregional failures than the control group. Similarly, at two years, locoregional failure was reported in just 39% of the thoracic radiotherapy group, whereas it was reported in 26% of the control group.
Generally, small-cell lung cancer is characterized by early dissemination. However, it can spread to other areas of the body. The goal of radiotherapy is to kill cancer, but not cure it.
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