Cancer is a cellular anomaly that, according to the Global Cancer Observatory (GLOBOCAN), affects the lives of approximately 50 million people worldwide. One of the main factors responsible for the majority of cancer-related deaths is the spreading of cancerous cells from the primary tumor to other parts of the body, known as metastasis.
In this article, we will explore what metastasis is, how it occurs, and what are the main treatment strategies currently available.
What is metastasis and how does it occur in the body?
Metastasis can be understood as the process by which new tumors are formed in different regions of the primary tumor. This process, which is a set of cellular events, accounts for 90% of cancer-related deaths.
The study of metastasis is one of the main focuses of cancer research, with continuous efforts to better understand the molecular mechanisms involved in the process and develop new strategies to prevent and treat metastatic disease.
The concept of metastasis has been recognized for centuries in the world of medicine. However, in the 19th century, Dr. Stephen Paget formulated the “seed and soil” theory. The theory states that seeds (cancer cells) could only grow in fertile soil (tissues).
Metastases originate from disseminated tumor cells (DTCs) or from a group of cells that leave the primary tumor and have the ability to undergo phenotypic changes (epithelial-mesenchymal transition) that can confer advantages for their survival on the “route” to another organ.
However, the secondary sites that can undergo metastasis present a pattern. For example, for pancreatic cancer, there are regions of the body that have a higher frequency of metastases. These regions are:
Furthermore, it is important to note that not all cancers will metastasize. Metastasis follows some primary steps for the “colonization” process. One of the important steps in this process is the preparation of secondary sites (pre-metastatic niche preparation) in relation to the tumor, i.e., “preparing the ground”.
The preparation of the new microenvironment, which will receive DTCs, is a multi-step process. Primary tumors release significant amounts of extracellular vesicles and secretory factors that together induce vascular extravasation, extracellular matrix modification, and immune suppression.
The vesicles carry mRNA from genes that act in cell migration and metastasis processes. In addition, primary tumors can also release exosomes, which may contain miRNA (microRNA), which also act as promoters of invasion.
What are metastatic processes?
After the “preparation” phase, adjacent processes include (briefly):
Invasion: at this stage, tumor cells detach from their origin and begin to proliferate in nearby tissues, such as blood and connective tissue. To do this, tumor cells secrete enzymes that lyse the extracellular matrix, allowing for displacement to other tissues;
Intravasation: as cells permeate other tissues, they can enter nearby blood and lymphatic vessels. Once in the bloodstream, cells can invade other regions of the body;
Circulation: cancer cells circulate through the bloodstream or lymphatic system to other organs and tissues, such as lungs, liver, and bones.
Extravasation: a process where tumor cells leave the blood (or lymphatic) tissue and invade other tissues to form a new tumor mass;
Proliferation: after successful invasion into a new tissue, proliferation and the formation of a new tumor occur.
The formation of metastases depends on multiple stages, including invasion, intravasation, survival in systemic circulation, extravasation, and actual cell proliferation. Each of these stages requires cancer cells to overcome various barriers, including the extracellular matrix, blood vessels, and the immune system.
After breaking numerous homeostatic barriers, cancer cells arrive at a location and may enter a dormant state, proliferate, or undergo cell death. There is also evidence that dormancy may be immunomediated by T cells and natural killer (NK) cells, which can coat DTCs. However, the exact mechanism of how cells leave the dormant state to begin proliferating in a new tissue is still unknown to scientists.
Despite metastases presenting high rates of cancer-related deaths, not all cells can actually initiate proliferation in a new organ.
Common symptoms of metastasis in different organs include:
- Pain and fractures for bone metastases;
- Headache, seizures, and dizziness in cases of brain metastases;
- Difficulty breathing for lung metastases;
- Jaundice or swelling in the belly for intestinal metastases;
- Weight loss due to metabolic changes in the body.
There are several physiological and environmental factors that can increase the chances of developing metastasis. Additionally, some individuals may have a higher or lower risk of metastasis. In general, some factors include:
- Tumor characteristics: aspects such as size, tissue location, and tumor type are associated with the risk of metastasis. Generally, larger tumors that are in certain parts of the body may have a higher probability of metastasizing;
- Cancer stage: this factor is related to how advanced the tumor is. More advanced cancer has a higher probability of metastasizing;
- Lymphatic system: cancer cells can spread through the lymphatic system, and the presence of cancer cells in lymph nodes near the primary tumor can increase the risk of metastasis;
- Inflammation: chronic inflammation can create a favorable environment for the spread of cancer cells.
- Genetic predisposition: some genetic mutations can increase the risk of cancer and metastasis. For example, mutations in the BRCA1 and BRCA2 genes are associated with an increased risk of breast and ovarian cancer, and mutations in the TP53 gene are associated with an increased risk of many types of cancer;
- Age and overall health: Advanced age and poor health can increase the risk of metastasis.
The presence of any of these factors does not necessarily mean that metastasis will occur, but it may increase the likelihood of it happening.
Metastasis diagnostic and staging methods
Due to the previously mentioned tumor characteristics, cancer diagnosis can vary from person to person. Generally, diagnostic tests include:
Imaging exams, such as X-ray, computed tomography, magnetic resonance, and “positron emission tomography” (radioactive particle), which can aid in detecting metastases. These tests can indicate abnormal growths in numerous body parts, in addition to determining the extent of the disease;
Biopsy, which consists of the surgical removal of a small tissue sample followed by its microscopic analysis to evaluate the presence of oncotic cells;
Blood tests, which can be used to measure levels of oncotic markers or other agents indicative of cancer presence;
Molecular profiling analysis to check the tumor’s genetic composition. This strategy can help determine the best clinical management of the patient, as well as predict the possibility of metastasis.
Alongside these exams, there is also the “metastasis staging system”. This system is a set of evaluations used to describe the extent of the metastasis. In some cases, metastatic cancer may be limited to a single location or a small number of sites in the body, while in other cases, it may have spread widely throughout the body, affecting various organs and tissues.
The most commonly used staging system is the TNM system (from the English: Tumor, Node, Metastasis).
The TNM system assigns a number or letter to describe the size of the primary tumor (T), whether cancer has spread to nearby lymph nodes (N), and whether cancer has spread to distant organs or tissues (M).
The combination of T, N, and M provides an overall stage for cancer, ranging from stage 0 (in situ cancer) to stage IV (advanced cancer that has spread to distant organs).
In 1995, Hellman and Weichselbaum presented to the world a new understanding of metastasis and coined the term “oligometastatic cancer”.
This is a term used to describe cancer that has spread from its primary site to a limited number of distant sites, usually 1-3 metastases.
Unlike widespread metastatic cancer, where malignant cells have spread to various body locations, oligometastatic cancer is believed to represent an intermediate stage in cancer progression.
Understanding the molecular mechanisms of these tumor subtypes can help in the development of new therapies targeted at metastases.
Metastasis treatment options
The treatments applied for metastases are, in principle, the same as those for the primary tumor. However, the choice of approach for treatment will be based on various factors. In addition, treatments are applied based on the individual needs of each patient.
Approaches to treatment may include:
Surgery: used to remove metastatic tumors if they are well-located and have not spread to other regions of the body. In addition, surgical methods can be applied to primary tumors and, consequently, slow down the progression of metastasis;
Radiation therapy: cancerous cells can be eliminated through radiation. It is also applied in cases of localized metastases that have not spread. In addition, symptoms such as pain can be relieved through radiation therapy.
Chemotherapy: treatment in which therapeutic compounds are used to contain cancer;
Immunotherapy: treatment that uses cells of the immune system, which are collected from the patient and subsequently modified to attack cancerous cells. It can be used to treat certain types of metastatic cancer, such as melanoma and lung cancer.
Targeted therapy: Targeted therapy uses drugs that specifically target cancer cells and spare healthy cells. It can be used to treat certain types of metastatic cancer that have specific genetic mutations.
Hormonal treatment: There are some types of cancers (such as prostate and breast) that use hormones to proliferate. This method uses applications that interfere with the behavior of hormones.
Palliative care for patients with metastasis
Although the term refers to the terminal stage of a particular disease, palliative care is also a form of treatment for patients with metastatic cancer.
These care practices are recognized by the WHO (World Health Organization), which defines them as assistance mediated by a multidisciplinary team that aims to mitigate pain and other physical, social, and psychological symptoms.
Some of the key aspects of palliative care for patients with metastatic cancer include:
Symptom management: The goal of palliative care is to relieve symptoms associated with cancer, such as pain, nausea, and fatigue. Palliative care specialists can provide medications and other therapies to effectively control these symptoms.
Emotional support: Patients with metastatic cancer often experience feelings of anxiety, depression, and fear. Palliative care specialists can provide emotional support and counseling to help patients cope with these emotions.
Communication and decision-making: Palliative care specialists can help patients and their families with difficult decisions about treatment options, end-of-life care, and other important decisions.
Spiritual and cultural support: Palliative care can also provide support to patients and their families based on their spiritual and cultural beliefs.
Preventing metastasis and healthy habits
But are there any actions or habits we can have to prevent the spread of cancer in our body?
It may seem obvious but perhaps not widely practiced, the habit of regularly seeing a doctor can help with early detection of cancer and, consequently, metastasis. When cancer is detected at an early stage or stages that can be controlled, the risk of metastasis is lower and therapies for treatment may have less intense side effects.
In addition, lifestyle matters! Habits such as smoking, unprotected sun exposure, consuming ultra-processed foods, and various other habits contribute to the development of cancer.
So, even if it seems difficult or tiring, try to lead a healthier life. See a doctor, exercise, drink water. In addition to reducing the risks of developing cancer, your self-esteem will also improve.
Unfortunately, metastasis is an aggressive characteristic present in many types of cancer. Although preventing metastasis is a significant challenge due to the molecular mechanisms involved, there are still some measures we can take for ourselves. And, such measures are associated with the lifestyle we lead.
But, there is a light at the end of the tunnel: research on new treatments and therapies for metastatic cancer continues. Every day, a new insight, a new discovery. And, for a cruel disease like cancer, every step is essential.
We, scientists, will not give up the arduous fight to find a definitive cure. And, there is also an appeal to those affected and to society as a whole: do not give up on science.
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