BREAKTHROUGHS IN CANCER METASTASIS COULD MEAN THE END OF TUMOR SPREAD

Metastasis has long since been a hard-hitting medical mystery that has plagued cancer patients and oncologists alike. The spread of tumor cells throughout the body substantially increases cancer mortality rates and often stands in the way of effective diagnostics and treatment.

Research in the last few years has allowed for several promising new avenues for preventing the spread of tumors, including the identification of drugs that can target tumor metastases. If current investigations are successful, we may be on the verge of drastically improved outcomes for those with cancer and a rise in survivorship.

The following article sheds light on the latest advancements in treating and preventing metastasis.

How Does Metastasis Work?

Theories surrounding metastasis have been recorded as early on as 1869. We now know that it is the result of rogue tumor cells that break off from the primary tumor site and make their way around the body through blood vessels and the lymphatic system.

Metastatic tumors can then be “seeded” by the “parent” or primary tumor, causing the formation of smaller secondary tumors at other parts of the body. The cells found in the secondary tumors are not different from those found in the primary tumor, which is how an oncologist can tell metastases apart from another primary tumor in a different location.^[1]

Metastasis Indicates Late-Stage Cancer. When metastatic tumors are found, the primary cancer is regarded as being late-stage or stage IV. Many of the most aggressive cancers are only diagnosed as a result of metastases, often being difficult to confirm otherwise due to their location, such as in the lungs or brain. Sadly, when metastasis occurs, it often increases the risk of patient mortality by as much as 90%.

The Prevalence of Metastases is difficult to pinpoint as it depends on the cancer type and its rate of growth. According to data published on the UK NHS website, the presence of stage 3 and 4 cancers vary between 9-84% for men and 11-75% for women at the time of diagnosis.

Current Treatments. Most current chemotherapies do not sufficiently tackle metastatic cancer and generally revolve around targeting the primary tumor and contributing factors. In some cases, treatment can help control the growth and spread of cancer in a similar manner to the primary cancer, which can improve survival outcomes. Unfortunately, over 90% of cancer deaths are still ascribed to metastasis, even with the progress seen in recent years. The new discoveries discussed below shed light on how a few current therapeutics may either help or hinder metastasis.

Recent Breakthroughs That Allude to New Prevention and Treatment Strategies

Despite progress, metastasis is still a rather elusive process. New scientific discoveries are discussed below that are expected to improve outcomes for patients.

Circulating Tumor Cell Clusters. Recent breakthroughs in metastatic oncology research have revealed more about how circulating tumor cells go on to metastasize at distant body sites. It is now understood that these rogue tumor cells are capable of forming clusters (CTCs) in the bloodstream, fusing together and/or with platelets or white blood cells, similarly to how proteins aggregate.

The following points highlight key findings that have helped in pinpointing novel therapies that can target CTCs, reduce metastasis risk and improve cancer survival:

• CTC Size and Lifespan Increase Metastases Risk. Circulating tumor cells typically undergo a type of “lifecycle” in which they grow larger and undergo changes that eventually allow them to become implantable in foreign tissues.^[2] Generally speaking, the longer they are in circulation, the larger they can grow, increasing their risk for metastasis. Clusters of tumor cells have proven to pose a risk of 23-50 times higher than single cancer cells for metastasizing at other body sites.^[3] They are noted to be more prolific in early-stage than late-stage cancer, where metastases have already occurred.
• Immune Cells Are Both Pro and Anti Metastasis. While more research is required to verify, it is suspected that the lymphocytes and neutrophils found in circulating tumor cell clusters contribute towards metastasis through releasing factors that stimulate inflammation and cancer growth^[4]. Targeting faulty immune cells and the products they release may help to inhibit the formation of CTCs and metastatic tumors. On the other hand, CTCs are able to evade immune detection just like primary cancer cells. Treatments that enhance the immune detection of natural killer cells^[5] and other similarly “militant” immune cells may help to obliterate rogue cancer cells and lower metastasis risk.
• CTC Type and Differentiation Dictate Tissue Specificity. When cells mutate into cancer cells, there are a broad range of mutations, some of which are generalized to many types of cancer and others that are tumor-type specific. Circulating cancer cells usually share the same genetics as the parent cells found in the primary tumor, however, less specific mutations have also been uncovered in the cells of larger CTCs. The higher the degree of non-specificity, the higher the risk of metastasis, due to less specific requirements for tissue implantation (see patterns of metastases below).
• Dormant Metastatic Cells and Recurrence Risk. Studies have shown that rogue cancer cells may be present in organs and tissues prior to the onset of primary cancer. These cells can go dormant for decades and may be involved in the growth of both primary and metastatic tumors upon activation.^[6] Cancer cell dormancy and activation can also partially explain why primary and metastatic cancer rates are higher in the elderly; both due to lifetime accumulation as well as the presence of senescent cells (which may more easily switch into cancer cells than ordinary ones).

Drugs to Target Circulating Tumor Cells in Breast Cancer. Researchers have found several drugs that are able to dissolve circulating tumor cell clusters as well as impair their ability to aggregate and metastasize^[7]. While initial evidence provides hope for the future of cancer patients everywhere, more clinical trials are required to confirm their effectiveness and appropriate dosing. A few of these drugs include:

• Cardiac Glycosides. Also known as Na+/K+-ATPase inhibitors, cardiac glycosides are a class of drugs that have been shown to inhibit metastasis through dissolving clusters of circulating tumor cells before they have a chance to metastasize^[8]. They are originally prescribed to patients for treating heart failure, serving to increase heart contractility. Preliminary evidence has shown promise for two common heart failure prescriptions, ouabain and digoxin, in lowering CTC levels. Earmarked as a recent breakthrough in metastasis treatment, Digoxin is currently undergoing stage I trials for its effectiveness in breast cancer metastases prevention.
• Zileuton was recently identified as a complementary chemo drug due to its ability to block cancer stem cells and completely eradicate CTCs in triple negative breast cancer in mice^[9]. They are particularly effective at blocking the contributions of neutrophils to metastases, through inhibiting arachidonate 5-lipoxygenase. Phase I and II clinical trials are currently underway to test similar effects in patients with Chronic Myeloid Leukaemia and lung cancer. As it is conventionally prescribed to treat asthma (especially aspirin-induced asthma)^[10], it may be more favorable than other anti-metastatic agents for those with respiratory problems.
• Anticoagulants. As CTCs are formed through cellular aggregation, it logically follows that anticoagulants may have anti-metastatic benefits. Previous research has shown that both warfarin and heparin can help to reduce the occurrence of metastases as well as promote enhanced survival outcomes in those with lung cancer.^[11] Not all anticoagulants proved to yield the same effects, and the effects appear to vary across cancer types. The risk of bleeding, particularly in the context of gliomas^[12], has postponed clinical trials until further notice. Nevertheless, cancer patients using blood thinners for other reasons may be at a reduced risk for metastasis.
• NSAIDs are becoming a leading avenue for enhancing cancer treatment outcomes. Plenty of reviews have highlighted that cancer rates are lower in NSAID users, and of those that do contract the disease, survival outcomes were improved. NSAID use is also associated with a greatly reduced risk of metastases across several types of cancer, with the exception of those located in the lymph node.^[13] The benefit appears to pertain to the multiple effects of NSAIDS, including their ability to lower a wide range of inflammation types^[14], thin the blood, inhibit metastatic CTCs, and radically reduce their presence in the bloodstream.

Medications that May Increase CTCs and Metastases Risk. Further endeavors to understand CTCs have revealed that various medications may add or detract from their growth and implantation. Some recent research has indicated that long-term use of currently available chemo drugs may mistakenly appear to lower circulating tumor cell levels, while in actuality, they may be contributing towards reducing their detection, increasing their resistance and promoting metastasis. Of these, long-term use of bevacizumab and monoclonal antibody denosumab have been implicated for promoting such effects. In a separate trial, administered insulin, metformin and ACE inhibitors were associated with elevations of metastatic CTCs in those with stage I-III breast cancer.^[15] Time will tell what other drugs may be contraindicated in cancer patients with respect to metastatic risk.

Surgical Incisions Increase Metastases Risk. Studies show that any incisions into the tumor may increase the risk of it spreading, with unfavorable implications for surgeries and biopsies. While not news, the latest research into CTCs has contributed undeniable evidence to support prior observations amongst cancer patients. Surgical incisions into the tumor site literally slough off cancer cells, releasing them into the circulation. Other variables contribute towards their clustering and metastases, such as anesthetics, transfusions, surgical complications, elevations in inflammation, as well as vascular growth and adhesion factors.

In this respect, the use of surgery and biopsy in cancer treatment and diagnostics is about to be challenged. Changes to be expected in the next couple of years include:

• Surgery Benefits May Supersede Risks. Despite these alarming results, many oncologists and other experts have rationalized the use of surgeries in various cases, such as when the tumor begins to physically impact the function of surrounding organs or tissues. If the full tumor can be removed, it may lower metastatic risk, however, data indicates that this is not usually the case^[16]. It has been shown that even a few cancer cells left behind may result in cancer resurgence years later with a higher risk for metastasis. This risk is expected to become greatly reduced with the advent of antimetastatic agents, as discussed above.
• Liquid Biopsy to Replace the Standard. The recent work highlighting CTCs development has not only brought to attention the major flaws inherent in conventional biopsy. It has simultaneously proposed an award-winning diagnostics solution: the liquid biopsy. Liquid biopsies are already being used to test for the presence of various blood cancers. However, as circulating tumor cells and clusters are detectable in the blood at all cancer stages, the refinement of liquid biopsies could replace the diagnostic standard. Currently, there is one FDA-approved test kit for CTCs, yet this form of testing is acknowledged to be in its infancy. In the coming years, better CTC sensitivity will likely refine diagnostics by allowing physicians to trace the stage and type of cancer without needing to inflame the tumor.^[17]

Patterns of Metastases to Revolutionize Treatment Protocols. Analysis of metastatic tumors reveals that there may be a common pattern that pertains to discrete tumor types. Metastasis most often occurs in the liver, lungs and bone.^[18] The heart and skin appear to be the least common sites for tumor migration, while muscle tissue is hardly ever affected. Cancers of the digestive tract often metastasize in other digestive organs, with the exception of the spleen.^[19] The number of body sites that harbor secondary tumors is another trend common to various types of cancer.^[20]

These findings suggest that metastases favors specific tissues which have reduced anti-cancer immune screening and defense mechanisms against the specific tumor type in question. This supports the use of precision chemotherapeutics for the treatment and prevention of metastases, depending on how they affect CTCs. It also highlights the need for investigating tumor-specific treatments for preventing metastases that target the suitability of distant body sites for harboring secondary tumors. This is known as correcting the tumor micro-environment. As it applies equally to primary tumor sites, it can explain why some chemotherapeutics also reduce metastasis risk. Possible targets include lowering tissue hypoxia, correcting pH and lowering tumor-specific inflammation across tissues.

Dietary Nutrients May Lower Metastasis Risk. While most informed cancer patients opt for a diet higher in nutrients known to lower inflammation and potentially enhance chemotherapy, research is now suggesting that the same nutrients may be able to inhibit the formation of CTCs, prevent cancer cell migration and reduce metastatic risk^[21]. Lower metastases occurrence is seen in breast cancer patients that consume nutrient-dense diets^[22], with in vitro experiments confirming the metastatic inhibiting properties of phytochemicals at diet-appropriate concentrations^[23].

Conclusion

While efforts have been primarily focused on primary cancer prevention and treatment, metastasis is known to stand behind the vast majority of cancer-related mortality. Contrary to prior understanding, new evidence suggests that metastatic processes may underpin the occurrence of both primary and metastatic tumors, further highlighting the importance of prevention. Recent breakthroughs in the field of metastasis have revealed that several common drugs and dietary nutrients may be beneficial in enhancing chemotherapy outcomes, while certain forms of chemo may even exacerbate metastatic processes. Less invasive diagnostic and treatment approaches are likely to lower metastasis risk and improve patient survival.