2 Liver Cancer and Angiogenesis

2 Liver Cancer and Angiogenesis

Abundant blood vessels are a key characteristic of tumors, and angiogenesis reflects the tumor's ability to grow and metastasize, playing a decisive role in tumor development. Liver cancer is a solid tumor rich in blood vessels. In recent years, inhibiting angiogenesis has become a hot topic in anti-tumor research, particularly in combating liver cancer (and other tumors). As early as 1836, scholar Virchow studied and proved that tumor tissues and surrounding areas exhibit coiled, dilated blood vessels with increased numbers. Later, in 1945, Algire first introduced the concept of "tumor angiogenesis" or "vascular neoformation," gradually realizing that vascular formation comprises two parts: angiogenesis and vasculogenesis, and that tumor growth is achieved through angiogenesis. This marked a milestone in the field of tumor angiogenesis research. In 1971, Folkman proposed the theory that "tumor growth depends on its angiogenesis," arguing that sustained tumor growth and metastasis rely on angiogenesis to provide sufficient nutrients to tumor cells. If the supply of tumor blood vessels is cut off, the tumor tissue will enter a dormant state or regress, shrinking to 1–2 mm; conversely, if angiogenesis continues, the tumor volume will grow exponentially [16][17]. Therefore, inhibiting tumor angiogenesis can not only reduce the size of the primary tumor, even causing it to disappear, but also suppress distant metastasis.

Tumor angiogenesis occurs under specific environmental conditions, influenced by both internal and external factors, resulting in a multi-step biochemical cascade mediated by various related cytokines. How angiogenesis is regulated is still under investigation; currently, the most clearly understood theory is the "angiogenesis switch balance hypothesis"—a dynamic equilibrium between pro-angiogenic and anti-angiogenic factors in tumor cells and the surrounding matrix [18–20]. Modern research on inhibiting angiogenesis focuses on blocking the regulatory cytokines and key steps involved in tumor angiogenesis, thereby curbing the process. Tumor angiogenesis involves the following aspects: [1] Tumor tissues produce multiple pro-angiogenic cytokines, increasing their activity and disrupting the balance between pro- and anti-angiogenic factors; [2] Under the influence of pro-angiogenic factors, endothelial cells undergo morphological and structural changes (increased number of organelles, enlarged cell bodies, and the appearance of pseudopodia); [3] Both tumor cells and endothelial cells release proteases, which degrade the basement membrane of capillaries and the extracellular matrix surrounding tumor cells, reshaping the extracellular matrix; [4] Endothelial cells migrate from surrounding capillaries to post-capillary venules, proliferate, and form new vascular buds that extend outward; [5] Finally, microvessels in the tumor tissue differentiate and take shape. In normal tissues, the formation of new blood vessels is regulated by a dynamic balance between pro- and anti-angiogenic factors, maintaining equilibrium. Both types of factors play important roles in tumor angiogenesis. However, in tumor tissues, pathological secretion of pro-angiogenic factors disrupts this balance, leading to abnormal formation of new blood vessels. Specifically, when the concentration of pro-angiogenic factors increases and that of anti-angiogenic factors decreases, tumor angiogenesis is promoted; conversely, when anti-angiogenic factors dominate, tumor angiogenesis is inhibited, directly affecting tumor growth and metastasis. Modern research shows that many tumors express basic fibroblast growth factor and vascular endothelial growth factor, both of which closely influence the phenotype of tumor angiogenesis. Other identified pro-angiogenic factors include angiopoietin (Ang), epidermal growth factor (EGF), matrix metalloproteinase (MMP), transforming growth factor (TGF), tumor necrosis factor (TNF), platelet-derived growth factor (PDGF), etc.; anti-angiogenic factors include interleukin-12 (IL-12), angiostatin, platelet factor 4, endostatin, thrombospondin (TSP), etc., all of which play a role in tumor angiogenesis.

Liver cancer is a highly vascularized tumor with a high potential for metastasis and recurrence, and angiogenesis plays a crucial role in its growth and spread. Newly formed blood vessels promote tumor growth by providing necessary nutrients and essential cytokines to liver cancer cells, while their incomplete structure also facilitates intrahepatic metastasis and opens the door for extrahepatic metastasis. Angiogenesis plays a pivotal role in the malignant biological process of liver cancer. Regulating angiogenesis in liver cancer is a complex process involving multiple factors, with pro-angiogenic and anti-angiogenic factors playing the most important roles. Therefore, the most promising area of modern research in treating liver cancer is how to inhibit angiogenesis, thereby cutting off nutrient supply, depriving cancer cells of oxygen and blood, preventing them from proliferating, and ultimately achieving therapeutic effects. Pei's Soft Liver and Anti-Plaque Pill enhances the body's immunity, effectively inhibits the growth and metastasis of liver cancer, is less likely to develop drug resistance, reduces the toxic side effects of radiotherapy and chemotherapy, and enhances their efficacy, among other benefits. This study aims to explore the efficacy of Pei's Soft Liver and Anti-Plaque Pill from the perspective of angiogenesis, testing whether it affects the factors that promote and inhibit tumor angiogenesis.

3 Traditional Chinese Medicine's Understanding of Primary Liver Cancer