Some cancers are difficult to beat, even with modern drugs. It is extremely difficult to find the right drugs to treat a cancer; cancer cells are particularly good at evading everything that modern medicine throws at them.
Many cancers, including Childhood Cancers are still treated with Radiation Therapy and/or Chemotherapy. but new research shows that one type of chemotherapy actually provides a safe haven for tumour cells, boosting cancer recurrence and growth in the long-run.
A good chemotherapy is meant to stop or slow the growth of a tumour; this is achieved by activating a pathway called programmed cell suicide, or apoptosis. Some cancer types however are resistant to apoptosis so other avenues must be pursued to destroy those tumours.
One alternative is to actually damage the DNA genetic code within the cancer cells to the point where it is beyond repair; the cells then respond by activating a process called cellular senescence.
Senescence was discovered more than 50 years ago and is thought to be a state of irreversible growth arrest, meaning that the cells stay where they are but do not grow any further.
Senescence however, turned out not to be the fool-proof method of eradicating cancer that some had hoped. Researchers have found a missing piece of the puzzle that could explain why senescence might actually provide a breeding ground for cancer stem cells, leaving the way open for tumours to grow back and spread.
In an article published in the journal Frontiers in Oncology, Markus Schosserer, Ph.D. — an assistant professor at the University of Natural Resources and Life Sciences in Vienna, Austria, explained that senescence is important in embryogenesis, wound healing, and the natural aging process. Senescence can also be harnessed to send cancer cells into a state that can be likened to extended sleep in that the cells are alive but not dividing.
“The basic arguments about the role of senescence in cancer protection are as follows: senescent cells have lost the ability to undergo cell division permanently, although they may be metabolically fully active,” writes Prof. Schosserer. “This would certainly protect individuals carrying a primary cancer from further cancerous growth.”
Schosserer adds that it is not as simple as that though – there is evidence that senescent cancer cells can secrete molecules that cause inflammation and promote a rich environment for cancer to grow back.
Dr. Clemens A. Schmitt, a professor in the Department of Haematology, Oncology, and Tumour Immunology at Charité-University Medical Center and the Max-Delbrück-Center for Molecular Medicine, both in Berlin, Germany — presented their recent breakthrough research findings in the journal Nature recently.
The scientists used lymphoma tumour cells from mice, treating them with drugs to induce senescence; the cells stopped dividing, as expected, but they also started to resemble specific stem cells and started to express genes — such as p21 and p53 — that are vital for maintaining stem cell functions, the collective name for which is “stemness.
Stemness is a massive problem in cancer because cancer stem cells are thought to drive the recurrence and spread, or metastasis, of tumours. Even though the cells do not divide, stemness speeds up cancer growth!!
The researchers also found evidence of this senescence-associated stemness in other cell models of cancer, and, crucially, they detected these cells in tumour samples from patients with primary B-cell chronic leukaemia, as well.
Prof. Schmitt’s team then released the cancer cells from senescence, using genetic manipulation to see if they would re-enter the normal process of cell division – they started to multiply within a few days – much faster than cells that had not undergone senescence!
When the team transplanted these previously senescent cancer cells into mice, very few cells were needed to kick-start the development of new lymphoma tumours. This shows that when cells that have acquired stemness escape senescence, they become highly cancerous.
The researchers also found evidence that cancer cells can escape senescence, identifying significantly more previously senescent stem cells in tumour samples of patients after lymphoma recurrence than were present in the same individuals when they received their initial treatment.
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An introduction to what cancer is and how it is the by-product of broken DNA replication. Created by Sal Khan.
Prof. Schmitt explains, “These results have important clinical implications, since they give us hitherto unknown insights how tumor cells […] evade, in principle, very effective anti-cancer therapies.”
“Fortunately, we were able to present […] genetic and pharmacological approaches that directly target the newly acquired cancer stemness of previously senescent cells and neutralize its functional benefit for tumor growth,” he adds.
The team found that a particular stem cell signaling pathway — called Wnt — is activated when senescent cells develop stemness. When the researchers switched off the Wnt pathway, either by adding a drug or by genetic manipulation of one of the genes in the pathway, tumor growth was reduced.
In an accompanying article in the journal Nature, Jan Paul Medema — a professor of experimental oncology and radiobiology at the Cancer Center of Amsterdam in the Netherlands — notes, “[The] data provide compelling evidence in the systems they studied that, when cancer cells escape from senescence, they have an enhanced capacity to drive tumor growth — a finding that has potential clinical implications.”
“In future experiments and a clinical trial we are currently conceptualizing, we will address the role of senescence-associated reprogramming in our lymphoma patients and seek to exploit a specific treatment strategy against it.” Prof. Clemens A. Schmitt