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Cancer and Signal Transduction


Cell signal transduction refers to the binding of extracellular factors to a receptor (membrane receptor or nuclear receptor), triggering a series of biochemical reactions and protein interactions in the cell, until the genes which required for cellular physiological reactions begin to express and the process of forming biological effects. It is now known that there is a variety of signal transduction methods and pathways in cells, and there are multiple levels of cross-regulation between various methods and pathways, which are a very complicated network system. Among information molecules, it can be classified into water-soluble information molecule and fat-soluble information molecule. Water-soluble information molecules and prostaglandins (liposoluble) must first bind to the membrane receptor, initiate a cascade of intracellular signal transduction, transduce extracellular signals transmembrane into the intracellular; fat-soluble information molecules can enter the cell and bind to cytoplasmic receptors or nuclear receptors to induce a cell-specific response by altering the transcriptional activity of the target gene.

The environment in which higher organisms live is changing all the time, and the coordination of the functions of the organism requires a perfect mechanism for mutual recognition, response and interaction between cells. The mechanism is called cell communication. In this system, cells recognize cells in contact with them, or recognize various signals present in the surrounding environment (from surrounding or distant cells) and transform them into functional changes in various molecules within the cell, thereby changing certain metabolic processes within the cell, affecting the growth rate of the cells, and even inducing cell death. The ultimate goal of signal transduction is to permit the body to respond appropriately to the changes in the environment at an overall level. In the regulation of material metabolism, it is frequently involved in the regulation of the metabolic pathway at the overall level by the neuro-endocrine system. The essence is that a part of the cell in the body emits signals, and another part of the cells receive signals and transforms them into changes in cell function.

Therefore, signal transduction will directly affect the regulation of cell proliferation, differentiation, metabolism and death. These functions of cells are closely relevant to cell carcinogenesis and tumorigenesis. With the discovery of oncogenes and tumor suppressor genes, the elucidation of cell signaling pathways has greatly increased the ability of cognizance of cellular carcinogenesis. Through the analysis of the function of oncogene products, it was found that many oncoproteins are located in different parts of the normal cell signal transduction pathway and play an important role in promoting cell division and proliferation. In the process of tumor development, due to normal gene regulation disorders, abnormalities in cell signaling network can be caused.

The Related Signaling Pathway with Cancer

Hedgehog (Hh) signaling pathway: Hedgehog signaling pathway is a signal transduction pathway that regulates embryonic development. It is closely related to the occurrence and development of human tumors. Abnormal activation of the Hedgehog signaling pathway can lead to the formation of a variety of tumors, such as basal cell carcinoma, medulloblastoma, small cell lung cancer, pancreatic cancer, prostate cancer, gastrointestinal malignancy, and the like. The Hedgehog signaling pathway is mainly composed of three parts: Hh signal peptide (Shh, Ihh, Dhh), transmembrane receptor (Ptch, Smo) and downstream transcription factor (Gli). Under normal conditions, the Hh protein is bound to the surface of the cell surface by its N-terminal lysate (Hh-N) produced by self-cleavage combined with cholesterol or a fatty acyl group. The activation of the Hedgehog signaling pathway is through the binding of ligand Hh to the transmembrane protein Pteh, which in turn releases the inhibition of Ptch on another transmembrane protein Smo, and Smo further controls gene transcription through the downstream transcription factor Gli.

Wnt signaling pathway: the Wnt signaling pathway is an evolutionarily conserved signaling pathway that plays a key role in embryonic development and the formation of the central nervous system. At the cellular level, it takes part in regulating cell growth, migration and differentiation. Current studies have shown that Wnt signaling pathway abnormalities exist in breast cancer, colorectal cancer, gastric cancer, liver cancer, melanoma, endometrial cancer, and ovarian cancer. The Wnt signaling pathway is mainly divided into three types: (I) the classical Wnt signaling pathway: nuclear translocation via β-catenin can activate the transcriptional activity of the target gene. (2) Cell-plane polar pathway: This pathway involves RhoA protein and Jun kinase. And it mainly controls the development time and space of the embryo. At the cellular level, this pathway regulates cell polarity by rearranging the cytoskeleton. (3) Wnt/Ca2+ pathway: this pathway induces an increase in intracellular Ca2+ concentration and activates Ca2+-sensitive components of signaling transduction. Tumors can occur when these pathways are repressed or over activated.

Tyrosine Kinase Receptor Pathways: Tyrosine kinases (PTKs) catalyze the transfer of γ phosphate group of ATP to tyrosine residues of many important proteins, thereby activating proteins. PTKs are transmembrane-structured enzyme protein receptors with tyrosine kinase activity in the inner segment of the cell. The extracellular domain binds to the growth factor ligand and then activates the intracellular domain of the enzyme active region. PTKs activation signals control the activity of many target molecules in the cell, including Ras/MAPK, STAT, JNK, P13K, and can also modulate the activity of transcription factors. One of the intracellular signaling pathways activated by PTKs is that the phosphorylated receptor binds to a downstream target, and then the mitogen-activated protein kinase(MAPK) and the phosphoinositide-3-kinase (PI3K) /AKT kinase pathway be activated. MAPK is a signal that promotes cell division, and PI3K/AKT kinase is a signal that promotes cell apoptosis and survival. Therefore, the final result of PTKs catalyzing receptor phosphorylation is to promote cell proliferation and inhibit apoptosis. These functions are directly related to the occurrence and development of tumorigenesis.

Studies have shown that the expression of protein kinases such as bcr-abl, EGFR, HER and PKC is abnormally increased in tumor patients, and they all belong to the category of PTKs. In particular, EGFR is overexpressed in a variety of malignant tumors such as glioma, breast cancer, lung cancer, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, prostate cancer, liver cancer, colon cancer, and gastric cancer. Activation of EGFR will accelerate tumor cell proliferation, promote tumor blood vessel growth, accelerate tumor metastasis, and impede tumor apoptosis.

Transforming growth factor-β pathway: transforming growth factor-β (TGF-B) regulates cell growth, differentiation and cell death, and promotes the extracellular matrix synthesis and angiogenesis, and inhibits the body's immune response and other biological functions. So the pathway has a close relationship with the occurrence and development of tumors. Interestingly, studies show that TGF-β appears to be two different or even opposite effects in the occurrence and development of tumors. In the early stages of tumors, it acts as a tumor suppressor due to its effect on cell cycle arrest; during tumor progression, TGF-β can be produced by tumor cells and/or surrounding stromal cells, and TGF-β lose the function of inhibited proliferation. In the late stage of tumor growth, TGF-β acts as a tumor promoting factor, providing microenvironment for tumorigenesis by stimulating angiogenesis, cell dissemination, immunosuppression and synthesis of extracellular matrix. A number of studies have shown that breast cancer, gastric cancer, colon cancer, prostate, bladder cancer, endometrial cancer and cervical cancer have high expression of TGF-β.

Nuclear factor-KB signaling pathway: nuclear factor-kB (NF-kB) signal transduction pathway belongs to proteolytic enzyme-dependent receptor signal transduction pathway. It closely relates to tumor cell occurrence, proliferation, differentiation, apoptosis, invasion and metastasis. Studies have shown that the continuous activation of NF-kB factor can be used as a marker for solid tumors such as breast cancer, ovarian tumor, colon cancer, pancreatic cancer, thyroid cancer, biliary tumor and prostate tumor.

Integrin transduction pathway: integrin is widely distributed and belongs to the family of cell adhesion molecules. Studies have found that integrins regulate adhesion between cells and between cells and extracellular matrix (ECM). Thereby, integrin mediated interactions between tumor cells and ECM, and affect tumorigenesis, proliferation, invasion, and the ability to metastasize to other tissues.

Although there is a deep understanding of the function of a single signaling transduction pathway and its relationship to tumorigenesis, intracellular signal transduction is not a single one-to-one relationship. They cross each other to form a complex network, and the same protein can participate in different pathway and plays a different role. Its molecular mechanism needs further exploration to provide protection for the development of anti-tumor drugs.


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