coaxing cancer cells to self-destruct (or at least get old and die)

[Lani]

Flip of genetic switch causes cancers in mice to self-destruct, Stanford researchers find
By Louis Bergeron

STANFORD, Calif. — Killing cancerous tumors isn’t easy, as anyone who has suffered through chemotherapy can attest. But a new study in mice shows that switching off a single malfunctioning gene can halt the limitless division of tumor cells and turn them back to the path of their own planned obsolescence.

The surprising possibility that a cell’s own natural mechanism for ensuring its mortality could be used to vanquish tumors opens the door to a new approach to developing drugs to treat cancer patients, according to Dean Felsher, MD, PhD, associate professor of oncology and of pathology at the Stanford University School of Medicine. Felsher is the senior author of the study published July 30 in the advance online version of the Proceedings of the National Academy of Sciences.

“Our research implies that by shutting off a critical cancer gene, tumor cells can realize that they are broken and restore this physiologic fail-safe program,” said Felsher.

Cancer can be notoriously resistant to medical treatment. Not only do cancer cells proliferate uncontrollably, they somehow circumvent the mechanism that causes normal cells to die when they get old or malfunction. That makes cancer cells effectively immortal unless doctors manage to squelch them.

The gene Felsher’s team studied produces a protein called Myc (pronounced “mick”), which promotes cell division. A mutation of the gene causes cells to overproduce the protein, prompting perpetual cell division and tumor growth. By turning off the mutated gene, the researchers found that not only did uncontrolled cell division cease, but the cells also reactivated a normal physiological mechanism, called senescence, which makes it possible for a cell to eventually die.

“What was unexpected was just the fact that cancer cells had retained the ability to undergo senescence at all,” said Felsher. Cancer researchers had long thought the senescence process had to be irreversibly disrupted for a tumor to develop.

The researchers worked with a series of mice engineered to have Myc-triggered cancers of either the liver, blood or bones, along with a specially constructed version of the Myc gene that they could switch off by feeding the mice antibiotics. When the mice dined on doses of the drugs, invariably, the tumors ceased growing and then diminished, with some disappearing over the course of just a few days.

Although Felsher’s lab had previously shown that mouse tumors diminished and disappeared when Myc was switched off, they hadn’t been sure how the process actually worked. Historically, most research involving genetic methods of battling cancer cells has focused on reactivating genes called tumor-suppressor genes, which are generally overcome by a proliferating cancer. No one had explored the idea that senescence might play a key role in diminishing tumors.

Felsher described senescence as acting like a fail-safe mechanism to stop cancer. When a cell detects a deleterious mutation, it launches the senescence process, resulting in the permanent loss of the cell’s ability to proliferate, thus halting any cancer.

“In order to become tumor cells, those cells have to overcome senescence,” said Chi-Hwa Wu, PhD, postdoctoral researcher in Felsher’s lab and first author of the study. Wu had the inspiration to explore whether the sudden diminishment they had observed in the tumors might be due to the reactivation of some latent remnant of the trigger for senescence.

Through a series of experiments looking at enzymes associated with the senescence process, as well as some molecular markers, Wu confirmed her suspicion. And not only was senescence occurring in cells that had been thought to be incapable of it, the process was reactivated in all the different tumors they studied.

Consider it a cell version of the Jekyll-and-Hyde transformation. “It’s sort of like Mr. Hyde realizing that there’s something wrong with him and then being able to put himself back into his normal state as Dr. Jekyll,” Felsher said.

In addition to the deepened understanding of how the process of senescence works, Felsher and Wu see a lot of potential for new approaches to treating cancer, beyond the traditional tactic of trying to kill cancer cells directly. “This work implies that maybe part of the strategy should involve figuring out how to get the cancer cells to just be allowed to do what they originally wanted to do anyway, which is to not be proliferating endlessly and growing uncontrolled,” said Felsher.

[Adriana Mangus]

Dear Lani:

This sounds even more exciting than the vaccine -Clinical Trials under way @ Mayo Clinic.

I know in my heart that there will be -if not a cure- a total novel way of controlling the growth of cancer cells, rendering them dead on the spot-just like Raid does to cockroaches.... je je Being a little silly just happy that there are so many clinical trials and new drugs under way to help us deal with this nasty disease.

Thank you so much for keeping us informed.

With deepest appreciation.

[R.B.]

Thanks for posting this Lani.

Do you have a link for it please. Is myc the same as c-myc?


Many thanks

RB

[Lani]

Flip of genetic switch causes cancers in mice to self-destruct, Stanford researchers find [Stanford School of Medicine]
STANFORD, Calif. — Killing cancerous tumors isn't easy, as anyone who has suffered through chemotherapy can attest. But a new study in mice shows that switching off a single malfunctioning gene can halt the limitless division of tumor cells and turn them back to the path of their own planned obsolescence.
The surprising possibility that a cell's own natural mechanism for ensuring its mortality could be used to vanquish tumors opens the door to a new approach to developing drugs to treat cancer patients, according to Dean Felsher, MD, PhD, associate professor of oncology and of pathology at the Stanford University School of Medicine. Felsher is the senior author of the study published July 30 in the advance online version of the Proceedings of the National Academy of Sciences.
"Our research implies that by shutting off a critical cancer gene, tumor cells can realize that they are broken and restore this physiologic fail-safe program," said Felsher.
Cancer can be notoriously resistant to medical treatment. Not only do cancer cells proliferate uncontrollably, they somehow circumvent the mechanism that causes normal cells to die when they get old or malfunction. That makes cancer cells effectively immortal unless doctors manage to squelch them.
The gene Felsher's team studied produces a protein called Myc (pronounced "mick"), which promotes cell division. A mutation of the gene causes cells to overproduce the protein, prompting perpetual cell division and tumor growth. By turning off the mutated gene, the researchers found that not only did uncontrolled cell division cease, but the cells also reactivated a normal physiological mechanism, called senescence, which makes it possible for a cell to eventually die.
"What was unexpected was just the fact that cancer cells had retained the ability to undergo senescence at all," said Felsher. Cancer researchers had long thought the senescence process had to be irreversibly disrupted for a tumor to develop.

ABSTRACT: Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation [Proceedings of the National Academy of Sciences]
Oncogene-induced senescence is an important mechanism by which normal cells are restrained from malignant transformation. Here we report that the suppression of the c-Myc (MYC) oncogene induces cellular senescence in diverse tumor types including lymphoma, osteosarcoma, and hepatocellular carcinoma. MYC inactivation was associated with prototypical markers of senescence, including acidic {beta}-gal staining, induction of p16INK4a, and p15INK4b expression. Moreover, MYC inactivation induced global changes in chromatin structure associated with the marked reduction of histone H4 acetylation and increased histone H3 K9 methylation. Osteosarcomas engineered to be deficient in p16INK4a or Rb exhibited impaired senescence and failed to exhibit sustained tumor regression upon MYC inactivation. Similarly, only after lymphomas were repaired for p53 expression did MYC inactivation induce robust senescence and sustained tumor regression. The pharmacologic inhibition of signaling pathways implicated in oncogene-induced senescence including ATM/ATR and MAPK did not prevent senescence associated with MYC inactivation. Our results suggest that cellular senescence programs remain latently functional, even in established tumors, and can become reactivated, serving as a critical mechanism of oncogene addiction associated with MYC inactivation.

[CLTann]

This truly is a facinating and important report on a new approach to cure cancer. I wonder is there any way we can do or help to get other researchers the attention this project deserves. I know there are many, many other research works being carried out in other labs throughout the world. However, we should voice our feeling to let these particular researchers know how we appreciate their work and would like to help in some constructive way.

[Gina]

Hi, Lani,

As usual, you are way out in front of the pack...smile. We are lucky to have you on OUR side...

I have been seeing other supporting documentation along the same lines you document in this thread and wondered if you had seen any documentation on the inverse relationship of her-2 and Tumor Necrosis Factor-alpha. TNF-alpha is a big player in generating normal cell apoptosis.

Basically if the her-2 protein increases, this causes, via a complex protein cascade that includes the proteins you mention above, Tumor necrosis factor-alpha to decrease which is not good, as the less TNF-alpha one has, the more cells can start becoming immortal--cancer like. The more TNF-alpha one has up to NORMAL limits of it, apoptosis or cell death, can easier occur, allowing the potential cancer cells to die a normal death. This is a proposed new means of how Herceptin may actually work, that hitherto, has not been elucidated.

What I am reading is suggesting...MIND YOU...only suggesting, that if you use Herceptin to down-regulate the her-2 over-expression, the TNF-alpha will come back up to normal levels on its own, all other things being equal of course, and apoptosis will happen automatically...that simple.

In my own 10 - year history with this illness, I have real life experience that would lead me to conclude that this is NOT too far off the mark. For instance, when I first had mets to the liver in 99, only 5 or 6 doses of Herceptin dropped my CA 27/29 tumor marker back into range and the twelve or so lesions on both lobes of my liver, the size of quarters, nickles and dimes, well, just simply disappeared. I have fortunately, or unfortunately as the case may be, been able to repeat this identical sequence of events 4 or 5 times now, using only varied doses of herceptin. Could it really be that simple??

It also makes me tend to agree with Believer? who posted something about us perhaps pulling out the big guns too soon in a recent post. For many years, I have thought that the hercepin alone would work better in some patients if the dose was targeted directly to the patients own tumor burden and not to some generalized protocol...but...sigh...smile..that is only me...smile... We have discussed and argued the point before, but I think that someone with say, a serum her-2 of 600 or more is in a totally different catagory than say someone with only 22 or so. To me, throwing the standard 2mg/kg weekly dose of Herceptin at the gal who has a tumor burden over 600 is like throwing a water balloon at a Towering Inferno, but still of course certainly way better that doing nothing at all...

Have any studies at all been done to individualize the HERCEPTIN DOSE to the tumor burden of the actual patients...or as Believer points out, are we just all too soon, reaching for the big guns????

In my own experience, her-2 levels have a mathematical symetry to uncontrolled cell - growth and reproduction patterns of bacteria--in other words, when the numbers go on a run, they tend to rise exponentially, the same way cells and bacteria tend to replicate.

Ideas any one??

Just wondering,
Gina

[Hopeful]

Gina,

I read a blurb last year that said the Baylor group had experimented with pre-operative Herceptin and reported that a low Ki-67 marker (which correlates to the proliferation rate) predicted for response to Herceptin. That, coupled with the recent findings that some Her2++ patients also responded to it, would give credence, IMO, to your theory about the proper dosing and its relationship to relative tumor burden being the key. The flip side of this is, what were the maximum toxicity levels tolerable for Herceptin? Part of the problem is the heart damage issue - Herceptin may work so long as you can get the tumor burden to a level that falls within the efficacy of the current dosing regimens. This may explain the "synergy" with chemotherapy.

Hopeful

[MichelleH]

Lani,

Thank you for such a interesting and promising article! I just love this site, so many of you come across great articles and pass them on to the rest of us!
Thanks again Lani!
Love,
Michelle