Metabolic factors that induce tumor development: obesity, insulin resistance, and the carcinogenic mechanism of adipokines

I. Overview A tumor is a new growth formed by the proliferation of local tissue cells under the influence of various carcinogenic factors. Because these new growths often present as space-occupying, mass-like protrusions, they are also called neoplasms. Research has found that tumor cells exhibit metabolic changes different from normal cells. Furthermore, tumor cells themselves can adapt to changes in the metabolic environment through the switching between glycolysis and oxidative phosphorylation (OXPHOS). Based on the cellular characteristics of the new growth and the degree of harm to the body, tumors are further divided into two main categories: benign tumors and malignant tumors. Malignant tumors can be divided into carcinomas and sarcomas. Carcinomas refer to malignant tumors originating from epithelial tissues. Sarcomas refer to malignant tumors arising from mesenchymal tissues, including fibrous connective tissue, fat, muscle, blood vessels, bone, and cartilage. For example, malignant tumors arising from the mucosal epithelium of the colon are called colorectal mucosal carcinoma, or simply colon cancer; those arising from the skin epithelium are called cutaneous carcinoma, or simply skin cancer. In the past few decades, the incidence of tumors and metabolic syndrome has increased rapidly worldwide. Cancer and metabolic syndrome severely impact people's health and quality of life. Metabolic syndrome is a collection of various metabolic risk parameters, including obesity, diabetes, dyslipidemia, and hypertension. Increasing evidence suggests a link between metabolic syndrome and increased cancer risk. Its mechanisms may involve multiple factors such as insulin, insulin-like growth factor-1, insulin resistance, estrogen, leptin, adiponectin, and inflammatory factors. Obesity is increasingly becoming a serious health problem in my country, with a rapidly growing obese population. Obesity is considered associated with various diseases, including cancer, and is closely related to the clinicopathological factors and prognosis of various cancers. In 2016, the International Agency for Research on Cancer (IARC) found sufficient evidence to support the association of excess body fat with 13 of 24 cancer sites, including: esophageal (adenocarcinoma), gastric cardia cancer, colon cancer, liver cancer, gallbladder cancer, pancreatic cancer, postmenopausal breast cancer, endometrial cancer, ovarian cancer, kidney cancer, meningioma, thyroid cancer, and multiple myeloma. II. Pathophysiological Changes

The mechanism of tumorigenesis: Tumor development occurs when, under the influence of various factors, cells in a local tissue lose normal regulation of their growth at the gene level, leading to abnormal cell proliferation and the formation of new growths. Tumors are genetic diseases; their biological basis is gene abnormalities. Pathogenic factors include somatic cell gene mutations leading to the loss of normal genes and disordered gene expression, thereby affecting the biological and genetic activity of cells and forming tumor cells that differ from normal cells in morphology, metabolism, and function. Tumor development is the result of multiple genes, multiple steps, and mutations. Different gene mutations and varying degrees of mutation intensity result in different types of tumors. Abnormal tumor morphology is the basis for tumor pathological diagnosis.

The molecular mechanisms linking obesity and cancer development are complex and not fully understood. Multiple factors may contribute to this relationship. In fact, obesity is often associated with metabolic abnormalities that not only promote cancer development but also its progression. These abnormalities include: low-grade inflammation of adipose tissue, oxidative stress, peripheral insulin resistance with hyperinsulinemia, and dyslipidemia. (1) Insulin resistance and hyperinsulinemia: Insulin resistance (IR) is a central link in metabolic syndrome. Patients with insulin resistance have impaired sensitivity to insulin, and their ability to promote glucose uptake and utilization by insulin is reduced, thus leading to hyperglycemia. In addition, as a compensatory mechanism, pancreatic β cells upregulate insulin production, thereby leading to hyperinsulinemia. Therefore, insulin resistance is often accompanied by hyperglycemia and hyperinsulinemia. It has been reported that the incidence of various tumors increases significantly when blood glucose is higher than 5.3 mmol/L. The mechanism may involve the effect of hyperglycemia on the growth and proliferation of tumor cells. Hyperglycemia can provide energy for the growth of tumor cells. The activity and glycolytic capacity of tumor cells are stronger than those of normal cells. Therefore, the hyperglycemic state is more conducive to the growth and proliferation of tumor cells. In addition, sugar can produce many reactive oxygen species during the decomposition and metabolism process, such as superoxide anions. Reactive oxygen species can promote the expression of vascular endothelial growth factor (VEGF) in tumors, thereby promoting microvascular angiogenesis. (2) Inflammatory response factors: More and more evidence shows that obesity can cause systemic inflammation, which may promote the development and progression of some malignant tumors. In the obese state, adipose tissue can produce inflammatory response factors such as TNF-α and IL-6. IL-6 is a pleiotropic cytokine that can interfere with cell growth and differentiation. Some results show that IL-6 may increase the risk of certain cancers, such as breast cancer, liver cancer, prostate cancer, colon cancer and esophageal cancer. TNF-α is mainly produced by macrophages and monocytes. It is a pro-inflammatory response factor that can participate in inflammatory and immune responses. TNF-α is also considered to be a cytokine that mediates tumor cell toxicity and is an effective inducer of new blood vessel growth. (3) Adipokines 1) Leptin: Leptin, also called OB protein, is also known as obesity suppressor. It is a multifunctional polypeptide secreted by adipose tissue and encoded by the obesity gene. Once leptin binds to its receptor, it can act on the hypothalamus to inhibit food intake and reduce appetite, as well as regulate insulin secretion and promote cell proliferation and angiogenesis. Some studies suggest that leptin may directly contribute to the progression of cancers, including breast cancer, thyroid cancer, and esophageal cancer. Leptin is structurally similar to certain cytokines, such as IL-2, IL-6, and granulocyte colony-stimulating factor (G-CSF), a property that allows it to participate in similar cellular response processes, such as controlling food intake, regulating energy expenditure, activating monocytes and macrophages, VEGF stimulation, angiogenesis, cell proliferation, and inhibition of anti-inflammatory cytokines. The induction of leptin responses and effects involves its binding to the leptin receptor β (ObR), leading to the activation of intracellular signaling via JAK2, STAT3, and AMPK. 2) Adiponectin: Adiponectin (APN), also known as adipocyte complement-associated protein, is a protein hormone derived from adipose tissue. It possesses various functions including anti-diabetic, anti-inflammatory, and anti-atherosclerotic effects. Unlike leptin's tumor-promoting effects, adiponectin has anti-tumor effects and is a protective factor closely related to the occurrence and development of MS. Adiponectin is negatively correlated with elevated inflammatory cytokines in obesity, such as TNF-α and IL-6; it can also attenuate NF-κB activation. 3) Resistin and Estrogen: Resistin is also an adipokine produced by human monocytes, macrophages, and adipocytes. Studies have found that resistin has multiple functions in the human body, participating in cell proliferation, anti-apoptosis, pro-inflammatory, and pro-angiogenic processes. Peripheral adipose tissue is responsible for the aromatization of steroids. Androgens and androgen precursors are converted to estradiol via aromatase. In cases of obesity and excess adipose tissue, aromatase activity increases, leading to increased conversion efficiency and consequently elevated estradiol levels. Estrogen receptors (ER) have two subtypes (α and β) with opposing effects on differentiated thyroid cancer (DTC): ERα promotes cancer cell proliferation, while ERβ promotes apoptosis and inhibits cancer cell proliferation.