These “Resistance” posts will be about the many ways that cancer becomes resistant to therapy. Check out a brief intro to why cancer is so hard to cure in my previous blog post. Cancer cells have plenty of ways to evade therapy, that’s why I think it’s worth to get an overview of the discovered mechanisms of cancer resistance. It might inspire me to think differently and identify ways to circumvent resistance down the line.
Discovery of senescence
This first blog post will be about senescence. Senescence is considered the state in which a cell has permanently stopped to divide. It is a stress response that is distinct from quiescence (= reversible cell cycle arrest), terminal differentiation and contact-inhibition. In 1961 Hayflick and Moorhead discovered that fibroblasts divide around 50 times before they stop to proliferate (1). This so-called “Hayflick limit” was later linked to shortening of telomeres with every cell cycle (2, 3). It was found that not only fibroblasts, but that non-cancerous cells in general across species and tissue origins, have a limited number of divisions after which replicative senescence is initiated (4). This was a groundbreaking discovery, because this means cells can’t divide forever!
Senescence as a barrier, preventing cancer development
Surprisingly, senescence does not only occur when the Hayflick limit is reached and replicative senescence is initiated. In 1997 the team of Scott Lowe discovered that overactivation of growth signals provided by so-called oncogenes, such as RAS can stop cells from dividing permanently (5). Their discovery suggested that senescence is not merely activated after a number of cell divisions, but is a protective program, triggered by abnormal levels of cellular growth signals. Around 2005 several labs found that in the stage before transforming into full-blown cancer, many cells are senescent (6, 7). This suggested that our bodies are trying to prevent cancer from developing by catching them into a non-dividing cell state, before it actually develops into full-blown cancer. Unfortunately, this isn’t always successful, and a cancer cell is still able to escape/bypass this mechanism of senescence leading to the development of cancer. Indeed, senescence is highly prevalent in the pre-stages of cancer. Once a cell has become cancerous, it is considered to have unlimited potential to divide, essentially becoming immortal.
Senescence in cancer
Even though cancer cells are considered to have an unlimited capacity for cell division, apparently, some cancers still have the capability to senesce! It appears that some cancers are better in suppressing senescence than other cancers. The question whether cancer cells can escape senescence after becoming senescent is still somewhat controversial, since there’s an ongoing debate about whether senescence is reversible. There is accumulating data that senescence is potentially reversible (8-12).
Senescence as resistance mechanism?
So how does all of this tie into resistance to therapies? It’s been shown that certain cancer treatments can damage cancer cells so much that they stop dividing and senesce, we call this therapy-induced senescence. A whole list of cancer treatments are known to induce senescence. Check out this splendid review by the Gerwitz’s lab for the long list of treatments (13). Recent evidence suggests that senescent cancer cells can make their non-senescent neighbouring cancer cells more aggressive and potentially resistant to cancer therapies (14, 15).
In short, senescence isn’t just a boring state of cells that aren’t dividing. Even the non-dividing cancer cells seem functionally relevant and can’t be ignored. It seems plausible that senescence itself can be a way to generate resistance in cancer cells. The mechanisms through which senescence can drive resistance needs more investigation.
(This is not a comprehensive review, simply for education and entertainment, so forgive me if I didn’t refer to your seminal discoveries)
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