Invasion and Metastasis - Pathophysiology of the Malignant Process

INVASION AND METASTASIS

Malignant disease processes have the ability to allow the spread or transfer of cancerous cells from one organ or body part to another by invasion and metastasis. Patterns of metastasis can be partially explained by circulatory patterns and by specific affinity for cer-tain malignant cells to bind to molecules in specific body tissue.

Invasion, which refers to the growth of the primary tumor into the surrounding host tissues, occurs in several ways. Mechanical pressure exerted by rapidly proliferating neoplasms may force fingerlike projections of tumor cells into surrounding tissue and interstitial spaces. Malignant cells are less adherent and may break off from the primary tumor and invade adjacent structures. Ma-lignant cells are thought to possess or produce specific destructive enzymes (proteinases), such as collagenases (specific to collagen), plasminogen activators (specific to plasma), and lysosomal hydro-lyses. These enzymes are thought to destroy surrounding tissue, in-cluding the structural tissues of the vascular basement membrane, facilitating invasion of malignant cells. The mechanical pressure of a rapidly growing tumor may enhance this process.

Metastasis is the dissemination or spread of malignant cells from the primary tumor to distant sites by direct spread of tumor cells to body cavities or through lymphatic and blood circulation. Tumors growing in or penetrating body cavities may shed cells or emboli that travel within the body cavity and seed the surfaces of other organs. This can occur in ovarian cancer when malignant cells enter the peritoneal cavity and seed the peritoneal surfaces of such abdominal organs as the liver or pancreas.

Metastatic Mechanisms

Lymph and blood are key mechanisms by which cancer cells spread. Angiogenesis, a mechanism by which the tumor cells are ensured a blood supply, is another important process.

LYMPHATIC SPREAD

The most common mechanism of metastasis is lymphatic spread, which is transport of tumor cells through the lymphatic circula-tion. Tumor emboli enter the lymph channels by way of the inter-stitial fluid that communicates with lymphatic fluid. Malignant cells also may penetrate lymphatic vessels by invasion. After en-tering the lymphatic circulation, malignant cells either lodge in the lymph nodes or pass between lymphatic and venous circulation. Tumors arising in areas of the body with rapid and extensive lym-phatic circulation are at high risk for metastasis through lymphatic channels. Breast tumors frequently metastasize in this manner through axillary, clavicular, and thoracic lymph channels.

HEMATOGENOUS SPREAD

Another metastatic mechanism is hematogenous spread, by which malignant cells are disseminated through the bloodstream. Hema-togenous spread is directly related to the vascularity of the tumor. Few malignant cells can survive the turbulence of arterial circu-lation, insufficient oxygenation, or destruction by the body’s immune system. In addition, the structure of most arteries and arterioles is far too secure to permit malignant invasion. Those malignant cells that do survive this hostile environment are able to attach to endothelium and attract fibrin, platelets, and clotting factors to seal themselves from immune system surveillance. The endothelium retracts, allowing the malignant cells to enter the basement membrane and secrete lysosomal enzymes. These en-zymes then destroy surrounding body tissues and thereby allow implantation.

ANGIOGENESIS

Malignant cells also have the ability to induce the growth of new capillaries from the host tissue to meet their needs for nutrients and oxygen. This process is referred to as angiogenesis. It is through this vascular network that tumor emboli can enter the systemic circu-lation and travel to distant sites. Large tumor emboli that become trapped in the microcirculation of distant sites may further metas-tasize to other sites. Research into ways to prevent angiogenesis is ongoing.

Carcinogenesis

Malignant transformation, or carcinogenesis, is thought to be at least a three-step cellular process: initiation, promotion, and progression.

In initiation, the first step, initiators (carcinogens), such as chemicals, physical factors, and biologic agents, escape normal enzymatic mechanisms and alter the genetic structure of the cellular DNA. Normally, these alterations are reversed by DNA repair mechanisms, or the changes initiate programmed cellu-lar suicide (apoptosis). Occasionally, cells escape these protective mechanisms, and permanent cellular mutations occur. These mutations usually are not significant to cells until the second step of carcinogenesis.During promotion, repeated exposure to promoting agents (co-carcinogens) causes the expression of abnormal or mutant ge-netic information even after long latency periods. Latency peri-ods for the promotion of cellular mutations vary with the type of agent and the dosage of the promoter as well as the innate char-acteristics of the target cell.

Cellular oncogenes, present in all mammalian systems, are responsible for the vital cellular functions of growth and differ-entiation. Cellular proto-oncogenes are present in cells and act as an “on switch” for cellular growth. Similarly, cancer suppres-sor genes “turn off” or regulate unneeded cellular proliferation. When the suppressor genes become mutated, rearranged, or am-plified or lose their regulatory capabilities, malignant cells are allowed to reproduce. The p53 gene is a tumor suppressor gene that is frequently mutated in many human cancers. This gene reg-ulates whether cells will repair or die after DNA damage. Mutant p53 gene is associated with a poor prognosis and may be associated with determining response to treatment. Once this genetic ex-pression occurs in cells, the cells begin to produce mutant cell populations that are different from their original cellular ancestors.

Progression is the third step of cellular carcinogenesis. The cel-lular changes formed during initiation and promotion now exhibit increased malignant behavior. These cells now show a propensity to invade adjacent tissues and to metastasize. Agents that initiate or promote cellular transformation are referred to as carcinogens.