The biology of tumor growth: having local infiltration and distant metastasis are the most important features of malignant tumors and are the main causes of death from malignant tumors. The natural growth history of a typical malignant tumor can be divided into several stages: malignant transformation of a cell → clonal proliferation of transformed cells → local infiltration → distant metastasis In this process, the intrinsic characteristics of malignant transformed cells (e.g. tumor growth fraction) and the host’s response to tumor cells and their products (e.g. tumor blood vessel formation) jointly influence the growth and evolution of the tumor. the growth and evolution of the tumor. (1) Kinetics of tumor growth. The growth rate of tumor is related to the following three factors: (1) Tumor cell ploidy time: the cell cycle of tumor population is also divided into G0, G1, S, G2 and M phases. Most malignant tumor cells do not have a faster ploidy time than normal cells, but are similar to or slower than normal cells. 2) Growth fraction: It refers to the proportion of cells in the tumor cell population that are in the proliferative phase (S phase + G2 phase). At the beginning of malignant transformation, the growth fraction is high, but as the tumor continues to grow, most of the tumor cells are in G0 stage, and the growth fraction is only 20% even for rapidly growing tumors. (3) Growth and loss of tumor cells: Insufficient nutrient supply, necrosis shedding, anti-tumor response of the body and other factors will cause loss of tumor cells. The generation and loss of tumor cells together affect whether the tumor can grow progressively and its growth rate. The growth rate of tumor is determined by the ratio of growth fraction and tumor cell production to loss, which has little relationship with the multiplication time. Almost all current chemotherapeutic drugs target cells in the proliferative phase. Therefore, tumors with high growth fractions (e.g., highly malignant lymphomas) are particularly sensitive to chemotherapy. Common solid tumors (e.g. colon cancer) have low growth fractions and are therefore not sensitive to chemotherapy. (2) Tumor angiogenesis. The ability to induce angiogenesis is one of the prerequisites for the growth, infiltration and metastasis of malignant tumors. Tumor cells themselves and inflammatory cells (mainly macrophages) infiltrating into and around tumor tissues can produce a class of angiogenic factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b–FGF). These angiogenic factors promote vascular endothelial cell division and capillary outgrowth. The nascent capillaries provide both nutrition for tumor growth and favorable conditions for tumor metastasis. (3) Tumor evolution and heterogeneity. The phenomenon that malignant tumors become more and more aggressive in the process of growth is called tumor evolution, including accelerated growth, infiltration of surrounding tissues and distant metastasis. The emergence of these biological phenomena is associated with tumor heterogeneity. Tumor heteroplasmy is the process by which tumor cells of one clonal origin form subclones that differ in invasive ability, growth rate, response to hormones, and sensitivity to anticancer drugs during growth. Due to these differences, tumors are able to retain those subclones that are adapted to survival, growth, infiltration and metastasis during the growth process. 2.Tumor growth mode: tumor can be expansive growth, exophytic growth and infiltrative growth. (1) Swelling growth: It is the growth mode of most benign tumors. The tumor grows slowly, does not invade the surrounding tissues, is often nodular in shape, has complete envelope, and has obvious demarcation with surrounding tissues, which mainly has the effect of extrusion or obstruction to the surrounding organs and tissues. Generally, they do not significantly damage the structure and function of organs. Because of its clear demarcation with the surrounding tissues, it is easy to remove surgically and not easy to recur after removal. (2) Exophytic growth: Tumors occurring on the surface of body surface, body cavity surface or the surface of pipeline organs (such as gastrointestinal tract, genitourinary tract) often grow towards the surface, forming protruding papillary, polyp-like, cauliflower-like swellings, benign and malignant tumors can grow exophytically. However, malignant tumors can grow exophytically while their bases are also infiltrating. Moreover, due to rapid growth and insufficient blood supply, exophytically grown malignant tumors are prone to necrosis and shedding to form malignant ulcers with uneven bases and elevated edges. (3) Infiltrative growth: It is the growth mode of most malignant tumors. As the tumor grows rapidly, it invades the surrounding tissues, lymphatic vessels and blood vessels, just like the roots of a tree growing into the soil, infiltrates and destroys the surrounding tissues, often there is no envelope or incomplete envelope, and the boundary between the tumor and the surrounding tissues is not obvious. During clinical palpation, the tumor is fixed and inactive. When surgically removing this kind of tumor, in order to prevent recurrence, the resection range should be larger than the range seen by naked eyes, because these parts may also have infiltration of tumor cells. 3. The spread of tumor is the main characteristic of malignant tumor. Malignant tumor with infiltrative growth can not only grow and spread in the primary site (direct spread), but also spread to other parts of the body through various ways (metastasis). (1) Direct spread: Tumor cells infiltrate along tissue interstices, lymphatic vessels, blood vessels or nerve bundles, destroy adjacent normal tissues and organs, and continue to grow, which is called direct spread. For example, advanced cervical cancer can spread to the rectum and bladder, and advanced breast cancer can cross the pectoral muscle and chest cavity and even reach the lung. (2) Metastasis: Tumor cells invade lymphatic vessels, blood vessels and body cavity from the primary site and migrate to other places and continue to grow, forming the same type of tumor as the primary tumor, this process is called metastasis. Benign tumors do not metastasize, only malignant tumors metastasize. The common metastatic pathways are as follows: 1) Lymphatic tract metastasis: malignant tumors of epithelial tissues mostly metastasize through lymphatic tract; 2) Hematological tract metastasis: all kinds of malignant tumors can occur, especially in sarcoma, kidney cancer, liver cancer, follicular thyroid cancer and choriocarcinoma; 3) Implantation metastasis: commonly found in carcinomas of abdominal organs. (4) Infiltration and metastasis mechanism of malignant tumors (l) Local infiltration The emergence of subclones of tumor cells with strong infiltration ability and the formation of intra-tumor blood vessels play an important role in local infiltration of tumors. The steps of local infiltration: 1) reduction of adhesion between tumor cells mediated by cell adhesion molecules; 2) tight attachment of tumor cells to basement membrane; 3) degradation of extracellular matrix. After 4–8 hours of close contact between cancer cells and basement membrane, the main components of extracellular matrix such as LN, FN, proteoglycans and collagen fibers can be lysed by proteolytic enzymes secreted by cancer cells, resulting in localized defect of basement membrane. (4) Cancer cells pass through the lysed basement membrane defect with amoebic motility. After crossing the basement membrane, cancer cells repeat the above steps to lyse the mesenchymal connective tissue and move through the mesenchyme. Upon reaching the vessel wall, they then cross the basement membrane of the vessel in the same manner to enter the vessel. (2) Hematogenous dissemination After entering the blood vessel, the majority of individual cancer cells are usually destroyed by the body’s immune cells, but the tumor cell clusters agglutinated by platelets are not easily destroyed and can cross the endothelium and basement membrane of the blood vessel through the above-mentioned pathway to form new metastases. The occurrence of metastases is not random, but has a clear organ predisposition. The location and organ distribution of hematogenous metastases have a special affinity in certain tumors, for example, lung cancer is prone to metastasis to the adrenal gland and brain, thyroid, kidney and prostate cancers are prone to metastasis to bone, and breast cancer often metastasizes to the liver, lung and bone. The reason for this phenomenon is unclear and may be due to the presence of ligands on the vascular endothelium of these organs that bind specifically to adhesion molecules on the surface of cancer cells entering the blood circulation, or due to the ability of these organs to release chemicals that attract cancer cells.