Metastasis: mechanisms

Metastasis is a pathogenic spread process, from an initial or primary site to a different or secondary site within the host’s body;[1]  Cancerous tumor are the best known.[2] The newly pathological sites, then, are metastases (mets).[3][4] It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.[5]

Cancer occurs after cells are genetically and metabolically  altered to proliferate rapidly and indefinitely. This uncontrolled proliferation by mitosis produces a primary heterogeneic tumour. The cells which constitute the tumor eventually undergo metaplasia, followed by dysplasia then anaplasia, resulting in a malignant phenotype. This malignancy allows for invasion into the circulation, followed by invasion to a second site for tumorigenesis.

Some cancer cells known as circulating tumor cells acquire the ability to penetrate the walls of lymphatic or blood vessels, after which they are able to circulate through the bloodstream to other sites and tissues in the body.[6] This process is known (respectively) as lymphatic or hematogenous spread.

After the tumor cells come to rest at another site, they re-penetrate the vessel or walls and continue to multiply, eventually forming another clinically detectable tumor. This new tumor is known as a metastatic (or secondary) tumor. Metastasis is one of the hallmarks of cancer, distinguishing it from benign tumors.[7] Most cancers can metastasize, although in varying degrees. Basal cell carcinoma for example rarely metastasizes.[7]

When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are similar to those in the original or primary tumor.[8] This means that if breast cancer metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells. The tumor in the lung is then called metastatic breast cancer, not lung cancer. Metastasis is a key element in cancer staging systems such as the TNM staging system, where it represents the “M”. In overall stage grouping, metastasis places a cancer in Stage IV.

With conventional oncology, the possibilities of curative treatment are greatly reduced, or often entirely removed, when a cancer has metastasized. In holistic oncology, when it’s successful, the immune system clears metastatic cells as well as the primary tumor’s cancer cells.

There is an ongoing  scientific debate on what constitutes the engines of metastases. Cancer stem cells (CSCs) would be one of these drivers. Metastasis progress via multiple cascade-drivers, including, but not limited to hypoxia,  ultraviolet radiation, inflammation (via the IL 8 pathway, inter alia), epigenetics , chromosomal instability, the tumor micro-environment , blood flow, circulatory tumor cells, angiogenesis, exosome vesicles and  macrophages, which would be the strongest pathway according to Professor Seyfried (observation collected from the ACR Institute’s video interview, part of which wwill be included in the ACR Institute’s documentary) . (Source)

“Macrophages are one of the most abundant immune cells in the tumour microenvironment of solid tumours and their presence correlates with reduced survival in most cancers. Macrophages are present at all stages of tumour progression and stimulate angiogenesis, tumour cell invasion, and intravasation at the primary site. At the metastatic site, macrophages and monocytes prepare for the arrival of disseminated tumour cells and promote their extravasation and survival by inhibiting immune-mediated clearance or by directly engaging with tumour cells to activate prosurvival signalling pathways. In addition, macrophages promote the growth of disseminated tumour cells at the metastatic site by organising the formation of a supportive metastatic niche. The development of agents inhibiting the recruitment or the protumorigenic effector functions of macrophages in both the primary tumour and at the metastatic site is a promising strategy to improve cancer survival in the future.” (Source)

While not miminizing macrophages and the other pathways, it would appear that exosome vesicles and cancer stem cells (CSCs) are key.  CSCs get attached to circulatory tumor cells (which are a little different from CSCs) in order to metastasize. (Source). Below, we  elucidate.

Generalities

The lungs, liver, brain, and bones are the most common metastasis locations from solid tumors.[9] In lymph nodes, a common symptom is lymphadenopathy Lungs: cough, hemoptysis and dyspnea[9] (shortness of breath) Liver: hepatomegaly (enlarged liver), nausea[9] and jaundice[9] Bones: bone pain,[9] fracture of affected bones[9] Brain: neurological symptoms such as headaches,[9] seizures,[9] and vertigo[9]

Although advanced cancer may cause pain, it is often not the first symptom. Some patients, however, do not show any symptoms.[9] When the organ gets a metastatic disease it begins to shrink until its lymph nodes burst, or undergo lysis.

Metastatic tumors are very common in the late stages of cancer. The spread of metastasis may occur via the blood or the lymphatics or through both routes.

The Metastatic Cascade

Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissues. By degrading these proteins, cancer cells are able to breach the ECM and escape. The location of the metastases is not always random, with different types of cancer tending to spread to particular organs and tissues at a rate that is higher than expected by statistical chance alone.[11] Breast cancer, for example, tends to metastasize to the bones and lungs. This specificity seems to be mediated by soluble signal molecules such as chemokines[12] and transforming growth factor beta.[13]

The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors, of which about a dozen are known.[14]

Human cells exhibit three kinds of motion: collective motility, mesenchymal-type movement, and amoeboid movement. Cancer cells often opportunistically switch between different kinds of motion. Some cancer researchers hope to find treatments that can stop or at least slow down the spread of cancer by somehow blocking some necessary step in one or more kinds of motion.[15]

Cancer researchers studying the conditions necessary for cancer metastasis have discovered that one of the critical events required is the growth of a new network of blood vessels, called tumor angiogenesis.[16] It has been found that angiogenesis inhibitors would therefore prevent the growth of metastases.[7]

Several different cell types are critical to tumor growth. In particular, endothelial progenitor cells have been shown to have a strong influence on the growth of tumor blood-vessels. Endothelial progenitor cells are also critical for metastasis and angiogenesis.[17][18] Endothelial progenitor cells are important in tumor growth, angiogenesis and metastasis, and can be marked using the Inhibitor of DNA Binding 1 (ID1). This novel finding meant that investigators gained the ability to track endothelial progenitor cells from the bone marrow to the blood to the tumor-stroma and even incorporated in tumor vasculature. Endothelial progenitor cells incorporated in tumor vasculature suggests that this cell type in blood-vessel development is important in a tumor setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow can lead to a significant decrease in tumor growth and vasculature development. Therefore, endothelial progenitor cells are important in tumor biology and present novel therapeutic targets.[19]

NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility as the basis of metastasis formation. Indeed, NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma[20][21] and NFAT3 (NFATc4) is an inhibitor of cell motility.[22] NFAT1 regulates the expression of the TWEAKR and its ligand TWEAK with the Lipocalin 2 to increase breast-cancer cell invasion [23] and NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.[22]

Epigenetic regulation also plays an important role in the metastatic outgrowth of disseminated tumor cells. Metastases display alterations in histone modifications, such as H3K4-methylation and H3K9-methylation, when compared to matching primary tumors.[24] These epigenetic modifications in metastases may allow the proliferation and survival of disseminated tumor cells in distant organs.[25]

A recent study shows that PKC-iota promotes melanoma cell invasion by activating Vimentin during EMT. PKC-iota inhibition or knockdown resulted an increase E-cadherin and RhoA levels while decreasing total Vimentin, phophorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggested that PKC-ι is involved in signaling pathways which upregulate EMT in melanoma thereby directly stimulates metastasis.[26]

Recently, a series of high-profile experiments suggests that the co-option of intercellular cross-talk mediated by exosome vesicles is a critical factor involved in all steps of the invasion-metastasis cascade.[27]

Metastasis occurs via multiple routes:

The spread of a malignancy into body cavities can occur via penetrating the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. For example, ovarian tumors can spread transperitoneally to the surface of the liver

Lymphatic spread allows the transport of tumor cells to regional lymph nodes near the primary tumor and ultimately, to other parts of the body. This is called nodal involvement, positive nodes, or regional disease. “Positive nodes” is a term that would be used by medical specialists to describe regional lymph nodes that tested positive for malignancy. It is common medical practice to test by biopsy at least one lymph node near a tumor site when carrying out surgery to examine or remove a tumor. This lymph node is then called a sentinel lymph node. Lymphatic spread is the most common route of initial metastasis for carcinomas.[7] In contrast, it is uncommon for a sarcoma to metastasize via this route. Localized spread to regional lymph nodes near the primary tumor is not normally counted as a metastasis, although this is a sign of a worse outcome. The lymphatic system does eventually drain from the thoracic duct and right lymphatic duct into the systemic venous system at the venous angle and into the brachiocephalic veins, and therefore these metastatic cells can also eventually spread through the haematogenous route.

This is typical route of metastasis for sarcomas, but it is also the favored route for certain types of carcinoma, such as renal cell carcinoma originating in the kidney. Because of their thinner walls, veins are more frequently invaded than are arteries, and metastasis tends to follow the pattern of venous flow. That is, hematogenous spread often follows distinct patterns depending on the location of the primary tumor. For example, colorectal cancer spreads primarily through the portal vein to the liver.

Some tumors, especially carcinomas may metastasize along anatomical canalicular spaces. These spaces include for example the bile ducts, the urinary system, the airways and the subarachnoid space. The process is similar to that of transcoelomic spread. However, often it remains unclear whether simultaneously diagnosed tumors of a canalicular system are one metastatic process or in fact independent tumors caused by the same agent (field cancerization).

The Seed and Soil Theory

There is a propensity for certain tumors to seed in particular organs. This was first discussed as the “seed and soil” theory by Stephen Paget in 1889. The propensity for a metastatic cell to spread to a particular organ is termed ‘organotropism’. For example, prostate cancer usually metastasizes to the bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer often metastasises to the ovary in women, then it is called a Krukenberg tumor.

According to the “seed and soil” theory, it is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics.[29] For example, breast tumor cells, which gather calcium ions from breast milk, metastasize to bone tissue, where they can gather calcium ions from bone. Malignant melanoma spreads to the brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo.[30]

In 1928, James Ewing challenged the “seed and soil” theory and proposed that metastasis occurs purely by anatomic and mechanical routes. This hypothesis has been recently utilized to suggest several hypotheses about the life cycle of circulating tumor cells (CTCs) and to postulate that the patterns of spread could be better understood through a ‘filter and flow’ perspective.[31]

However, contemporary evidences indicate that the primary tumour may dictate organotropic metastases by inducing the formation of pre-metastatic niches at distant sites, where incoming metastatic cells may engraft and colonise.[27]

Specifically, exosome vesicles secreted by tumours have been shown to home to pre-metastatic sites, where they activate pro-metastatic processes such as angiogenesis and modify the immune contexture, so as to foster a favourable microenvironment for secondary tumour growth.[27]

Epigenetics of Cancer Metastasis

The metastasis of cancer refers to the spread of the original (primary) tumor to a distant location in the body. Metastasis is a multi-step process: the cells must separate from the primary tumor, travel through the body to a new site through blood vessels or lymph vessels, reach a distant location, and then finally colonize the distant location to form a secondary tumor (Source) Proteins have been identified that work to block cancer spread. These metastasis suppressors, which can inhibit any step of the process of metastasis. Metastatic cancer cells have been shown to epigenetically silence metastasis suppressors, often by hypermethylating these genes. (Source)

The reasons why cancer cells metastasize is still not completely understood. Comparisons of the DNA sequences from metastatic cells and primary tumor cells were not always able to identify DNA sequence changes that could explain the difference between the cells. In 2017, researchers found an epigenetic basis for metastasis in at least one experimental model. This study examined pancreatic cancer cells from diseased patients and found that there were significant changes in the epigenome of metastatic cells, particular epigenetic changes that affected genes involved in cell migration.(Source)

Metastatic Growth may have no corresponding primary tumor

It is theorized that metastasis always coincides with a primary cancer, and, as such, is a tumor that started from a cancer cell or cells in another part of the body. However, over 10% of patients presenting to oncology units will have metastases without a primary tumor found. In these cases, doctors refer to the primary tumor as “unknown” or “occult,” and the patient is said to have cancer of unknown primary origin (CUP) or unknown primary tumors (UPT).[32] It is estimated that 3% of all cancers are of unknown primary origin.[33] Studies have shown that, if simple questioning does not reveal the cancer’s source (coughing up blood—”probably lung”, urinating blood—”probably bladder”), complex imaging will not either.[33] In some of these cases a primary tumor may appear later.

The use of immunohistochemistry has permitted pathologists to give an identity to many of these metastases. However, imaging of the indicated area only occasionally reveals a primary. In rare cases (e.g., of melanoma), no primary tumor is found, even on autopsy. It is therefore thought that some primary tumors can regress completely, but leave their metastases behind. In other cases, the tumor might just be too small and/or in an unusual location to be diagnosed.

The cells in a metastatic tumor resemble those in the primary tumor. Once the cancerous tissue is examined under a microscope to determine the cell type, a doctor can usually tell whether that type of cell is normally found in the part of the body from which the tissue sample was taken.

For instance, breast cancer cells look the same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry, FISH (fluorescent in situ hybridization), and others. Despite the use of techniques, in some cases the primary tumor remains unidentified.

Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor.

It was previously thought that most cancer cells have a low metastatic potential and that there are rare cells that develop the ability to metastasize through the development of somatic mutations.[34] According to this theory, diagnosis of metastatic cancers is only possible after the event of metastasis. Traditional means of diagnosing cancer (e.g. a biopsy) would only investigate a subpopulation of the cancer cells and would very likely not sample from the subpopulation with metastatic potential.[35]

The somatic mutation theory of metastasis development has not been substantiated in human cancers. Rather, it seems that the genetic state of the primary tumor reflects the ability of that cancer to metastasize.[35] Research comparing gene expression between primary and metastatic adenocarcinomas identified a subset of genes whose expression could distinguish primary tumors from metastatic tumors, dubbed a “metastatic signature.”[35] Up-regulated genes in the signature include: SNRPF, HNRPAB, DHPS and securin. Actin, myosin and MHC class II down-regulation was also associated with the signature. Additionally, the metastatic-associated expression of these genes was also observed in some primary tumors, indicating that cells with the potential to metastasize could be identified concurrently with diagnosis of the primary tumor.[36] Recent work identified a form of genetic instability in cancer called chromosome instability (CIN) as a driver of metastasis.[37] In aggressive cancer cells, loose DNA fragments from unstable chromosomes spill in the cytosol leading to the chronic activation of innate immune pathways, which are hijacked by cancer cells to spread to distant organs.

Expression of this metastatic signature has been correlated with a poor prognosis and has been shown to be consistent in several types of cancer. Prognosis was shown to be worse for individuals whose primary tumors expressed the metastatic signature.[35] Additionally, the expression of these metastatic-associated genes was shown to apply to other cancer types in addition to adenocarcinoma. Metastases of breast cancer, medulloblastoma and prostate cancer all had similar expression patterns of these metastasis-associated genes.[35]

The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential within the primary tumor and hope for improving the prognosis of these metastatic-associated cancers. Additionally, identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis.[35]

Treatment and survival is determined, to a great extent, by whether or not a cancer remains localized or spreads to other locations in the body. If the cancer metastasizes to other tissues or organs it usually dramatically increases a patient’s likelihood of death. Some cancers—such as some forms of leukemia, a cancer of the blood, or malignancies in the brain—can kill without spreading at all.

Once a cancer has metastasized it may still be treated with radiosurgery, chemotherapy, radiation therapy, biological therapy, hormone therapy, surgery, or a combination of these interventions (“multimodal therapy”). The choice of treatment depends on a large number of factors, including the type of primary cancer, the size and location of the metastases, the patient’s age and general health, and the types of treatments used previously. In patients diagnosed with CUP it is often still possible to treat the disease even when the primary tumor cannot be located.

Current treatments are rarely able to cure metastatic cancer though some tumors, such as testicular cancer and thyroid cancer, are usually curable.

Palliative care, care aimed at improving the quality of life of people with major illness, has been recommended as part of management programs for metastasis.[38]

Although metastasis is widely accepted to be the result of the tumor cells migration, there is a hypothesis saying that some metastases are the result of inflammatory processes by abnormal immune cells.[39] The existence of metastatic cancers in the absence of primary tumors also suggests that metastasis is not always caused by malignant cells that leave primary tumors.[40]

Discussion

Tumor metastasis accounts for most cancer-associated deaths in patients. During metastasis, tumor cells must disseminate, intravasate into circulation, travel through vascular networks, arrest in vascular beds of target organs, and subsequently extravasate into the organ parenchyma. In a hostile distant organ, they must escape host immune surveillance, adapt to supportive niches, survive as latent tumor-initiating seeds, and eventually break out to grow. Evidence from recent years strongly suggests that the tumor microenvironment (TME) is an indispensable participant in the metastatic process, allowing the tumor cells not only to escape from host immune surveillance, but also induce the formation of new blood vessels and invade the vasculature.

About the Seed and Soil Hypothesis

Early cancer researchers noticed a propensity for certain cancers to metastasize to the same organ.  In 1889 Stephen Paget observed that patients with breast cancer often developed secondary tumors in the liver.  He considered it unlikely that this occurrence was due primarily to accessibility of the liver by the blood supply, as other organs receiving equivalent blood supply rarely developed metastases.  He instead developed the “Seed and Soil” hypothesis, in which certain tumor cells (the seeds) can only successfully colonize selective organs (the soil) that have suitable growth environments. (Source)

The current view of the Seed and Soil Hypothesis consists of three important concepts.

Primary tumors and their metastases consist of genetically diverse tumor and host cells (for more on the role of the host cells in cancer, see the section on Tumor Microenvironment)

Metastasis selects for cells that can succeed in all phases of the metastatic process.  In essence, a successful metastatic cell must be a decathalete: good in all the events, and not just one or two.

Metastases generally develop in a site specific way.  Because the microenvironments (the soil) of each organ is different, individual cancer cells may be able to colonize one specific organ. (Source)

At the heart of the Seed and Soil hypothesis is the idea that successful metastasis depends on the interaction of the metastasizing tumor cells with the cells of the target organ (the stroma, or tumor microenvironment).  Not only must tumor cells be able to produce factors that alter the stromal cells in such a way as to better serve the survival and growth of the tumor, but the environment in which the cancer cell finds itself must be capable of responding to those signals.  If the cancer cell finds itself in an inhospitable soil (i.e. it cannot subvert the stroma to serve its needs), successful metastasis will be difficult. (Source)

More later

 

 Metastasis

Metastasis is the major cause of tumor lethality. However, not every tumor cell can metastasize. This potential depends on factors that determine growth, angiogenesis, invasion and other basic processes. In epithelial tumors, the epithelial-mesenchymal transition (EMT) is considered to be a crucial event.[78] EMT and the reverse transition from mesenchymal to an epithelial phenotype (MET) are involved in embryonic development, which involves disruption of epithelial cell homeostasis and the acquisition of a migratory mesenchymal phenotype.[79] EMT appears to be controlled by canonical pathways such as WNT and transforming growth factor β.[80]

EMT’s important feature is the loss of membrane E-cadherin in adherens junctions, where β-catenin may play a significant role. Translocation of β-catenin from adherens junctions to the nucleus may lead to a loss of E-cadherin and subsequently to EMT. Nuclear β-catenin apparently can directly, transcriptionally activate EMT-associated target genes, such as the E-cadherin gene repressor SLUG (also known as SNAI2).[81] Mechanical properties of the tumor microenvironment, such as hypoxia, can contribute to CSC survival and metastatic potential through stabilization of hypoxia inducible factors through interactions with ROS (reactive oxygen species).[82][83]

Tumor cells undergoing an EMT may be precursors for metastatic cancer cells, or even metastatic CSCs.[84] In the invasive edge of pancreatic carcinoma, a subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells was defined. These cells exhibited significantly stronger migratory activity than their counterpart CD133+CXCR4 cells, but both showed similar tumor development capacity.[85] Moreover, inhibition of the CXCR4 receptor reduced metastatic potential without altering tumorigenic capacity.[86]

In breast cancer CD44+CD24−/low cells are detectable in metastatic pleural effusions.[24] By contrast, an increased number of CD24+ cells have been identified in distant metastases in breast cancer patients.[87] It is possible that CD44+CD24−/low cells initially metastasize and in the new site change their phenotype and undergo limited differentiation.[88] The two-phase expression pattern hypothesis proposes two forms of cancer stem cells – stationary (SCS) and mobile (MCS). SCS are embedded in tissue and persist in differentiated areas throughout tumor progression. MCS are located at the tumor-host interface. These cells are apparently derived from SCS through the acquisition of transient EMT (Figure 7).[89]

 The concept of migrating cancer stem cells (MSC). Stationary cancer stem cells are embedded in early carcinomas and these cells are detectable in the differentiated central area of a tumor. The important step toward malignancy is the induction of epithelial mesenchymal transition (EMT) in the stationary cancer stem cells (SCS), which become mobile or migrating cancer stem cells. Stem cells divide asymmetrically. One daughter cell will begin proliferation and differentiation. The remaining MCS migrates a short distance before undergoing a new asymmetric division, or disseminates through blood vessels or lymphatic vessels and produces a metastasis.

In stem…file

Conclusion

In March 2014 researchers discovered the oldest complete example of a human with metastatic cancer. The tumors had developed in a 3,000-year-old skeleton found in 2013 in a tomb in Sudan dating back to 1200 BC. The skeleton was analyzed using radiography and a scanning electron microscope. These findings were published in the Public Library of Science journal.[41][42][43] Metastasis is a Greek word meaning “displacement”, from μετά, meta, “next”, and stasis, “placement”.

Text under construction

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