What is metastasis?

Metastasis is the spread of cancer cells from their original site to other parts of the body. Cancer cells detach, travel through the bloodstream or lymphatic system to other organs or tissues, and form new tumors, which consist of the same type of cancer cells as the original tumor. For example, if breast cancer spreads to the lungs, the lung tumor contains breast cancer cells.¹

Cancer invasion, in which cancer cells penetrate neighboring tissues directly adjacent to the original tumor, is often the first step in the metastasis process. Subsequently, cancer cells breach the walls of lymphatic or blood vessels, a process known as intravasation. This allows cancer cells to enter the circulation and spread either through the lymphatic system or via the bloodstream. Eventually, cancer cells adhere to the walls of blood vessels in distant tissues and invade a new site. If the cancer cells successfully adapt to this new environment, they will start to colonize it, developing a secondary tumor supported by newly formed blood vessels.²

Metastasis requires significant adaptation from cancer cells to survive in hostile environments. This often leads to their death unless they encounter favorable conditions at each step of the complex process.

Some types of cancer have a much lower probability of metastasizing than others. For example, basal cell carcinoma (BCC), the most common form of skin cancer, and certain types of thyroid cancer, such as papillary and follicular thyroid cancers, are less likely to metastasize.

Factors supporting cancer metastasis

One of the major conditions contributing to the spread of cancer cells is anaplasia, which is the return of cells to a primitive state where they feature poor differentiation or lack it completely. Differentiation is necessary for cells to develop distinct features and functions that support specific body tissues.

Anaplastic cells can vary in size and shape and are typically characterized by large, hyperchromatic (dark-staining) nuclei, a high nucleus-to-cytoplasm ratio, and frequent mitotic activity, which contribute to rapid tumor growth.³ Further anaplastic transformation is driven by genetic mutations in signaling pathways, such as the PI3K and MAPK pathways, which enhance tumor resistance not only to the body’s natural defense mechanisms but also to medical treatments.

Anaplastic cells can lose their adhesion properties, which normally keep cells tightly bound to each other and form the extracellular matrix. This loss of adhesion allows cancer cells to become mobile.

Usually, the spread of cancer cells occurs through single-cell migration. However, in certain scenarios, entire clusters of cells move together, which can accelerate metastasis.

Cancer cells develop various mechanisms to enhance their survival, which is crucial for their detachment from the extracellular matrix. One of them is their high adaptability in energy usage, allowing cancer cells to adjust to new environments. Another mechanism is platelet shielding, where cancer cells bind to thrombocytes (disk-shaped cell fragments responsible for blood clotting). This process helps cancer cells protect themselves from the immune system and physical forces in the bloodstream.

Common sites for cancer metastasis

Metastasis can affect almost any part of the body, with some organs being more susceptible to invasion by cancer cells depending on the type of cancer. It is common for metastatic cells to settle in the lymphatic nodes, especially if they enter circulation through the lymphatic system.

The liver, lungs, and bones are particularly vulnerable to metastasis and are frequently affected by cancers originating in the bladder, colon, kidney, ovary, pancreas, and breast, among others. Additionally, metastasis frequently occurs in the brain, peritoneum, skin, muscle tissues, and adrenal glands.

Cancer metastasis survival

Breast cancer metastasis is particularly common. Lung cancer, prostate cancer, colorectal cancer, kidney cancer, and melanoma are among the most prone to metastasize as well. However, metastatic cancer cells do not always form tumors after reaching a new site. In addition to the death of cancer cells in new environments, in some cases, they may also remain inactive for many years or never grow at all.

Factors that increase the likelihood of metastasis include:

• Larger tumors;
• Higher-grade tumors (those with faster growth rates);
• An auspicious microenvironment surrounding the primary tumor, especially the presence of blood vessels and the absence of immune cells;
• Low oxygen levels;
• A weakened immune system.⁴

The smaller the spread of cancer to other tissues, the higher the chance of effective treatment. However, most stage 4 cancers are not curable but are treatable, meaning they can be controlled by therapies to prolong survival. Effective cancer control often requires adjusting medications and treatments, as cancer cells can develop resistance.⁵

References:

1. “Metastasis” National Cancer Institute
   https://www.cancer.gov/publications/dictionaries/cancer-terms/def/metastasis
2. Majidpoor J. Mortezaee K. “Steps in metastasis: an updated review.” Medical Oncology. 2021. 38(3).
   https://doi.org/10.1007/s12032-020-01447-w 
3. Dr. Maho Yokoyama, Ph.D. “Features of Anaplastic Cells” News Medical Life Sciences
   https://www.news-medical.net/life-sciences/Features-of-Anaplastic-Cells.aspx
4. “Metastatic Cancer: When Cancer Spreads.” National Cancer Institute.
5. “What is metastatic cancer?” Canadian Cancer Society.
   https://cancer.ca/en/cancer-information/cancer-types/metastatic/what-is-metastatic-cancer