Cancer begins with uncontrolled cell multiplication, creating an abnormal growth. Metastasis is the process where malignant cancer cells detach from this original tumor and travel through the body to establish new growths in distant organs or tissues. This spread distinguishes a malignant tumor from a benign one, which remains localized to its initial site. Understanding the mechanisms of this dissemination is central to treating advanced-stage cancer, as metastasis is responsible for the majority of cancer-related deaths.
Distinguishing Primary and Secondary Tumors
The initial tumor, located where the cancerous cell growth began, is the primary tumor. This location dictates the cancer’s official name (e.g., lung cancer or breast cancer). A secondary tumor, also called a metastatic tumor, forms when cells from the primary site successfully colonize a distant part of the body.
The distinction lies in the identity of the cells, not the location of the new growth. If breast cancer cells form a tumor in the lung, the resulting growth is still classified as metastatic breast cancer, not lung cancer. This is because the cells retain the molecular and genetic characteristics of the original primary tumor cells. These cells look identical under a microscope to the primary cells, which guides diagnosis and treatment.
The Metastatic Cascade: A Step-by-Step Process
Metastasis is a highly selective, multi-step process known as the metastatic cascade; only a tiny fraction of cells successfully completes it. This complex sequence requires cancer cells to overcome numerous physical and biological barriers. The cascade begins with the cancer cells acquiring the ability to move through the surrounding tissue.
Local Invasion
The first step, local invasion, requires malignant cells to break away from the primary tumor and penetrate surrounding tissue. Cancer cells achieve this by changing shape and producing enzymes, such as proteases, which break down the extracellular matrix and the basement membrane. This process often involves epithelial-to-mesenchymal transition, a cellular change that grants the cells migratory capabilities and reduces adherence.
Intravasation
Following local invasion, cancer cells must enter the circulatory system, a step called intravasation. The cells push through the walls of local blood or lymphatic vessels to gain access to the body’s transportation networks. They often enter the circulation at the tumor’s edge, where vessels are more permeable due to the tumor’s growth and signaling.
Survival in Circulation
Once inside the bloodstream, circulating tumor cells (CTCs) must survive in a hostile environment. They face mechanical stress from blood flow and must evade detection and destruction by the immune system. Many CTCs travel in small clusters or are coated in platelets and fibrin, which acts as a protective shield against immune cells and physical damage.
Extravasation
After traveling through the circulation, CTCs must stop at a distant site and exit the vessel, a process called extravasation. The cells adhere to the inner lining of the blood vessel wall, often in small capillaries, and then push outward into the surrounding organ tissue. This step is the reverse of intravasation, allowing the cancer cells to leave the circulatory highway and enter the foreign organ environment.
Colonization
The final step is colonization, where cancer cells must adapt and proliferate in the foreign tissue to form a detectable secondary tumor. The vast majority of cells that successfully extravasate fail at this stage, as the new organ’s microenvironment is often incompatible with their growth. Successful colonization requires the cancer cells to create a supportive network of blood vessels and manipulate the local tissue environment for sustained growth.
Common Pathways and Target Organs
Cancer cells use two main routes to spread: the lymphatic system and the bloodstream (hematogenous spread). The lymphatic system is a network of vessels that carry lymph fluid and immune cells, and it is frequently the first route of spread for many solid tumors. Cells traveling through the lymphatic system often become lodged and form metastases in nearby lymph nodes.
The bloodstream provides a direct path to distant organs, and the pattern of spread is often determined by the anatomical drainage from the primary tumor site. For example, gastrointestinal cancers commonly spread to the liver because the portal venous system drains directly from the intestines to the liver. This mechanical route explains many frequent sites of metastatic deposit.
Despite the influence of blood flow, metastasis is not entirely random, a concept explained by the “seed and soil” hypothesis. Proposed in 1889, this theory suggests that metastatic tumor cells, or “seed,” can only successfully grow in a distant organ, the “soil,” if the environment is favorable. The soil must possess the necessary growth factors and supportive cells to nurture the invading cells.
This compatibility explains why certain cancers consistently target specific organs, known as organ tropism. The most frequent target organs for metastasis are the lungs, liver, bones, and brain, regardless of the primary tumor’s origin. The primary tumor can even prepare the distant site by sending signaling molecules and small vesicles called exosomes, which create a “pre-metastatic niche” that primes the soil for future colonization.