New research challenges current thinking on cancer
4open special issue presents a new paradigm for cancer
Imagine if we could understand and treat the root causes of cancer, rather than struggling to remove it or mainly treating its symptoms once it has already taken hold. The authors of a new peer-reviewed Special Issue of the open access journal 4open have paved the way for this vision by challenging our understanding of how cancer begins, develops, and spreads.
Entitled “Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm "Epistemology of the origin of cancer"”, the Issue reveals the robust evidence for their new hypothesis about the origin of cancer. The paradigm includes a chain of six events that together explain why the vast majority of cancers develop through complex alterations in cell signaling and communication, and why most cancers are not caused by mutations as commonly believed.
This concept will radically change how we perceive and treat cancer, and even allow us to prevent cancer in the first instance.
Genetic mutations cause cancer - or do they?
“We all learn in school that cancer is caused by genetic mutations that make our cells grow uncontrollably,” says Professor Björn Brücher, an author on the Special Issue. “This belief, although confirmed for only less than 10% of cancers, has become a dogma for the origin of all cancers.”
Clearly, something is amiss. The truth is that we know a lot less about what causes cancer than you might think. In fact, researchers don’t know what causes a massive 80% of cancers. While genetic mutations are present in many advanced cancers, there is no evidence that they caused the cancer, and likely occurred after the cancer had already begun. In most cancers, the somatic mutation hypothesis simply doesn’t stack up.
Despite this, “scientists have overwhelmingly focused on genetic mutations in their quest to understand the causes of cancer” says Dr. Ijaz Jamall and that “this has been a major hurdle to advancing cancer research, and means that we have missed opportunities to explore other possibilities.”
Current cancer treatment could be better
Our failure to understand the cause of most cancers has had real-world implications in terms of how we treat them. The most common treatment methods, including surgery, chemotherapy and radiotherapy, deal with the symptoms of cancer rather than its causes. These treatments are arguably crude and involve cutting the tumor out or attempting to kill the cancer cells using toxic drugs or radiation. This doesn’t always work, can have serious side effects, and may set the stage for secondary cancers years later.
Newer, more sophisticated treatments, such as immunotherapy can be effective in a few cancers, but still fail to address or reverse the root cause. In fact, we currently have no way to proactively prevent cancer in a targeted way, even for cancers for which we understand the cause. We are still not close to eradicating the disease, and the prevalence of many cancers is increasing.
A new cancer paradigm
However, not all researchers have focused exclusively on genetic mutations in the search to understand the origins of cancer. A small, but growing field of research has focused on exploring alternatives. Brücher and Jamall have developed an entirely new hypothesis for the origins of most cancers, which they first announced in 2014. This plausible cancer paradigm proposes a series of six events necessary for the 80% of cancers with unknown origins, and does not rely on mutations (https://www.karger.com/Article/FullText/443106).
Their hypothesis outlines a sequence of events that underlie the progression from healthy tissue to cancer. The Special Issue includes 10 papers that provide evidence to support this paradigm. One article entitled “Chronic inflammation evoked by pathogenic stimulus during carcinogenesis”, describes the biochemical and physiological signaling events involved in carcinogenesis in detail.
The process begins with a pathogenic stimulus, such as an infection, which causes inflammation in the affected tissue. Inflammation is a normal process during healing and usually resolves itself when an infection is over. This healing process is unsuccessful when the stimulus and inflammation are too great or too prolonged and the inflammation becomes chronic. Here, the disruptions that occur in biochemical and physiological homeostasis are complex, but this complexity provides many opportunities to block some of these pathways and thereby reduce the risk of developing cancer.
If chronic inflammation persists, it can cause fibrosis. Fibrosis is a process similar to scar formation where cells called fibroblasts grow and form fibrous tissue. As detailed in another article in the issue, “Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation, fibrosis caused by chronic inflammation drastically changes the cellular environment affected by it.
This altered cellular environment and accompanying changes in the levels of biochemical signaling molecules lead to a precancerous state. If the body’s attempts to escape this situation prove ineffective, then the affected cells may transition into cancer cells.
Inflammation and cancer
While it may seem strange to think of inflammation as part of the carcinogenic process, researchers have known about the link between inflammation and cancer for a long time. For example, chronic inflammation was first reported in testicular cancer in chimney sweeps in 1755. While researchers had previously observed the link between inflammation and cancer, no one had identified the complex multi-step processes involved and assembled them into a coherent hypothesis, until recently. This includes a dysregulation in homeostasis, which is the body’s tendency to maintain complex biochemical events within a range that maintains health.
Many carcinogenic substances cause inflammation and there are numerous examples of cancers linked to it. For instance, asbestos fibers cause inflammation and lung cancer, without genetic mutations. Hepatitis C infection can cause chronic inflammation in the liver, which can progress to liver cancer with no mutations. In patients with inflammatory bowel disease, the risk of cancer is increased 20 to 30-fold. Human papilloma virus acts in a similar manner to cause cervical cancer and oropharyngeal cancers.
Brücher and Jamall are not alone in recognizing the importance of inflammation in cancer others have also drawn attention to the link between infections in early life with the later risk of colon and breast cancer, and discussed the potential of anti-inflammatory drugs to reduce this risk.
What could this new paradigm mean for cancer patients?
The interplay between pathogens, inflammation, fibrosis, and cancer cell development involves a huge range of complex biochemical signaling molecules and aberrant cell behaviors. Untangling these relationships to discover the exact mechanisms involved is an ongoing process. However, rather than being a hurdle, this complexity affords an opportunity for cancer patients in the form of new treatment options, and potentially even preventative treatments.
“This cancer paradigm offers many processes that we could target to prevent and even reverse the process of carcinogenesis before it is complete,” explains Brücher. “For example, a drug that reduces inflammation or fibrosis could potentially prevent cancer from developing” states Jamall. Developing treatments that address the root causes of cancer could be a game changer for patients.
This approach could mean that cancer goes from a lethal disease to a disease of inconvenience, such as diabetes.
Given the importance of these findings, the authors are delighted to publish their peer-reviewed Special Issue in 4open, an open access journal, making information about this new paradigm more easily available to the public and researchers alike. Open access publishing is crucial for the widespread dissemination of ground-breaking ideas and results, allowing the scientific community to freely share new information that could change the course of research and medicine.
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