Cancer is one of the most dreaded diseases of our time and the second leading cause of death worldwide behind cardiovascular diseases. Cancer refers to any malignant growth or tumor in the body, caused by abnormal and uncontrolled cell growth in that specific spot. Cells are constantly renewing themselves, but when they get damaged in some way, the normal regular division of cells – with new cells forming and old ones dying off – goes haywire and cells in the affected area continue to divide and grow uncontrollably.
Cancer cells are living, reproducing cells that are capable of movement when not bound or restricted by other cells or structures. The capability to move is put to use when these cells require sustenance or when they must avoid danger. A process called cancer metastasis occurs when cancerous cells break off from a primary cancer tumor and spread through the bloodstream or lymph vessels to establish themselves in another part of the body. There these cells may grow and form other tumors, called secondary cancers. Metastasis constitutes the primary cause of cancer related death, with an estimated 90% of cancer patients dying due to metastases.
How cancer can spread to other areas:
A primary tumor sheds cancerous cells from the time it first forms and these cells are able to evade detection for months, years, or decades. Even after effective treatment for the primary tumor leaves a person cancer free, some of these cancer cells may be left behind.
Cancers are named according to where the primary tumor started developing. Breast cancer, for example, that has spread to the liver is called breast cancer with liver metastases and not liver cancer. The cancerous cells in the liver are breast cancer cells and not liver cells that have become cancerous. Cancerous cells circulate as single cells or in clusters, which are more likely to form metastases.
Spreading in the bloodstream: Cancer cells are able to move into small blood vessels and then into the bloodstream and are aptly called circulating tumor cells (CTC’s). They are swept along in the bloodstream until they get stuck somewhere, often in small blood vessels, such as a capillary. The cancer cell then has to move through the blood vessel wall and into the tissue of the nearest organ. When nutrients are available and conditions are favourable, the cell can multiply to form a new tumor. Of the many thousands of cancer cells that reach the bloodstream, very few survive to form a secondary cancer, as they face obstacles. Many die because they get battered around in the fast-flowing bloodstream, while others are killed by the white blood cells of the immune system.
Spreading in the lymphatic system: The lymphatic system consists of a network of tubes and glands, which filters body fluid and fights infection. It also traps harmful cells such as cancer cells. Cancer cells can go into the small lymph vessels close to the primary tumor and travel into the nearby lymph glands, where some may die, while others may survive and grow to form tumors in one or more of the lymph nodes.
Spreading through micro-metastases: This process refers to circulating tumor cells that are too small to see or show up on any type of scan. For a few types of cancer, there are blood tests that can detect certain proteins that are released by cancer cells. For most types of cancers, however, there are no blood tests available which can indicate whether the cancer has spread. In these instances, doctors can only indicate whether it is likely that the cancer has spread, based on previous experience, or whether there are cancer cells in the blood vessels or lymph nodes in a tumor that has been removed during surgery, or the grade of cancer which indicates the aggressiveness of the cancer and the likeliness of it spreading.
Clinical observations suggest that most cancers metastasize to specific target organs and this process is known as “metastatic organotropism”.
Reasons for cancer metastasis:
Cancer research has for some time focused on determining the mechanisms underlying cancer metastasis, with the aim of finding ways to inhibit this process. While these mechanisms explain the process of cancer metastasis, it does not explain why cancer would metastasize in the first place.
Some of the factors playing a role in cancer metastasis (especially when cancer cells move away from a hostile environment) are:
- Attack by the immune system – as a number of studies and clinical cares aim to prevent and treat cancer by enhancing the immune system, the paradox is that inflammation, resulting from the enhanced immune reaction, acts as a facilitator of cancer metastasis.
- Lack of oxygen and necessary nutrients – as cancer cells are capable of movement (motility), this is put to use when cells require sustenance or experience a hostile environment. Metastasis is suspected to occur when the primary tumor overgrows the ability of the blood circulatory system to supply sufficient nutrients.
- Increased cell death – as cancer cells are autonomous cells that have control over their own lives, increased cell death would stimulate the increase in numbers of surviving cells through cell division. In theory, under conditions of increased cell death, surviving cells are likely to move away.
- Large amounts of lactic acid are produced by glycolysis in cancer cells, which engage in glycolysis at a high rate. Lactic acid increases the acidity of the surrounding environment, resulting in cancer cells moving away from this hostile environment. Studies have indicated that low local PH stimulates cancer invasion and metastasis.
- The prevailing theory that cancer begins with genetic mutations and that metastasis shares the same origin, does not seem to be based on supporting evidence, as no single gene has yet been identified as responsible for metastasis.
- Scientists are having a shift in thinking, from viewing cancer as a genetic disease to viewing cancer as a metabolic disorder, with more of the latest research supporting this thinking.
- The concept of a tumor microbiome results from bacteria detected within tumors, although no links to cancer patient outcomes or cancer metastasis have so far been established.
- The circadian clock in the body controls a wide range of cellular processes and studies amongst night-shift workers have correlated circadian clock disruptions with cancer initiation and progression.
- Recent research suggests that a diet high in saturated fat can boost cancer metastasis. Increasing evidence indicates that lipid (fat) metabolism is enhanced at different stages of cancer development. The excessive consumption of food rich in fat, particularly high levels of saturated fat found in typical Western diets, as well as obesity, are risk factors for the development of metastasis. Animal studies have shown that high-fat diets can alter metabolism and cellular states in healthy tissues and predispose them to cancer.
- Popular belief has it that surgery to remove a tumor can stimulate cancer growth. However, metastasis after surgery probably arises from dormant cancer cells that have evaded elimination by the immune system, and which have already been present at the time of the surgery.
- Circulating tumor cells are subjected to the shear forces of the fast-flowing bloodstream and some of them are halted when their adhesive capacity becomes greater than the shear forces imposed on them, usually in regions with low blood flow pressure. For example, a study of 100 patients with cancer metastasis in the brain found that these metastases formed in regions with low cerebral blood flow.
- When circulating tumor cells pass through small capillaries, they can become entrapped, leading to either microvascular rupture, or leaking into the tissue around the blood vessel. Organs such as the liver and bone have highly permeable blood capillaries and exhibit a high rate of cancer metastasis.
- Cancer dormancy is an arrest phase in cancer progression. Metastatic dormancy results from the delayed acclimatization of cancer cells to their secondary positions.
- The brain is a special site for cancer metastasis, as the blood-brain barrier allows the crossing of circulating tumor cells but prevents the passage of therapeutic agents.
Conclusion :
Cancer metastasis remains the primary cause of cancer-related deaths. The development of effective therapeutic agents is hampered by a lack of clinical trials that target metastasis and a lack of knowledge of the exact biological underpinnings that govern the metastatic process.
Scientists need better ways to find and eliminate dormant metastatic cells, that could cause trouble in the future. Reducing cancer metastases is the key to curtailing the rate of death from cancer.
References:
Molecular principles of metastasis: A hallmark of cancer revisited. Published 12 March 2020 in the journal Signal Transduction and Targeted Therapy. Nature. (www.nature.com)
Metastasis. (Metastic cancer). Published online and last reviewed 24 April 2014. Cleveland Clinic. USA. (A nonprofit multi-specialty medical center that integrates clinical and hospital care with research and education.) (www.clevelandclinic.org)
How cancer can spread. Published online and last reviewed 9 October 2023. Cancer Research UK. (www.cancerresearchuk.org.)
When cancer spreads: Research focuses on better ways to treat metastasis. Published 1 December 2017. Memorial Sloan Kettering Cancer Center. USA. (www.mskc.org)
Reasons for cancer metastasis: A holistic perspective. Published 14 August 2015 in the journal Molecular and Clinical Oncology. PubMed Central. National Centre for Biotechnology Information. US National Library for Medicine. National Institutes of Health. USA. (www.ncbi.nlm.nih.gov)
The role of lipids in cancer progression and metastasis. Published 1 November 2022 in Cell Metabolism. Volume 34, issue 11, pages 1675 – 1699. Science Direct. (www.sciencedirect.com)
How dietary fats help cancer to spread around the body. Published online. Worldwide Cancer Research. (www.worldwidecancerresearch.org)
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