[Rhonda]: Cancer is another sort of very, it's been, in regards to autophagy, something
that I've always sort of been unsure about, because it's very clear to me that preventing
the accumulation of damage, you know, pieces of nucleic acid and pieces of chromatin and
all sorts of things that can cause inflammation by having damaged proteins around and things
like that.
Obviously, clearing those out would be very important for preventing cancer.
But when it comes to treating cancer, it's not as clear.
There seems to be...
I mean, for example, you know, there's a very classic drug out there, chloroquine, right,
that inhibits autophagy that's used to kill cancer cells.
But...
[Dr. Kroemer]: Well, it's not exactly [inaudible] or chloroquine is a lysosomal inhibitor.
It's a molecule that, due to its charge, will specifically enrich in the membranes of lysosomes,
and then causes lysosomal membrane damage, potentially also inhibition of autophagy.
But it fundamentally also liberates the potentially toxic content of lysosomes into the cytosolic
space.and so, there are a few reports around showing that inhibition of autophagy is not
the sole mechanism by which chloroquine can mediate such a toxic effects.
[Rhonda]: Okay.
Well, that's good to know.
[Dr. Kroemer]: The other thing that is important to notice is that chloroquine and hydroxychloroquine,
which are antimalarial agents that have been used for a long period, and also actually
used for the treatment of rheumatoid arthritis because they have anti-inflammatory properties.
Only introduced into clinical trials, most in combination with chemotherapy or radiotherapy
to treat cancer.
And those clinical trials, so far, are not convincing.
[Rhonda]: Okay.
So what about the fact that some cancer cells do activate autophagy?
[Dr. Kroemer]: So one relatively general mechanism may be that early during oncogenesis, the
deletion of tumor suppressor genes or the activation of oncogenes leads to autophagy
suppression.
So there are several examples for this.
And it is part of the process that leads to cellular transformation, because autophagy
is a homeostatic mechanism that, if inhibited, favors genomic instability and malignant transformation
of the cells.
So there are examples on the literature also that dived inhibition of autophagy is sufficient
to cause oncogenesis, in particular, in the context of leukemia.
And so, later on, when the cells strive and adapt to an ever more hostile microenvironment,
hostile because there's too little vascularization for the expanding cancer cells, so initially
there are hypoxic areas, there's no normal tissue architecture, so the cells are usually
undernourished.
The doctor may apply some chemotherapeutic agent which is an additional stress.
So there are internal and external stress pathways that the cell has to cope with.
And it is an advantage for the cancer cells to reactivate the autophagic process.
And so, it has been proposed that inhibition of autophagy would be a way to make the cancer
cells more fragile and vulnerable to therapeutic intervention by chemotherapy, radiotherapy,
targeted therapies.
The problem is that nothing is simple in oncology and that cancer is not just a cell-autonomous
disease.
It is more.
It is not just that one cell has become wild term and has been accumulating genetic and
epigenetic changes that make it selfish.
No, a cancer cell will only survive if it escapes from amino surveillance.
So the immune system, fortunately for us, is usually very efficient in eliminating aberrant
sells, premalignant cells, and the initial cancer cells.
And actually, the inhibition of autophagy that occurs during early oncogenesis maybe
also a way for the cancer cells to hide from the immune system.
And so, it is complex.
It's immunology, multiple different players come into action.
Autophagy, for instance, is required for stressed cells to release ATP into the microenvironment.
You know, of course, ATP is the most important, energy-rich metabolite in the cell.
It's like the equivalent of the dollar for bioenergy clinics in the economy.
And ATP, when it appears all of a sudden outside of the cell, is considered as non-physiological.
It is a dangerous signal.
It is perceived by so-called purinergic receptors that are present, among other cell types,
on leukocytes, and particularly myeloid cells.
And a cell that undergoes autophagy may, especially, when this occurs before cell death, release
ATP to attract myeloid cells into its proximity and to start an immune response against tumor
antigens in the context of the initial oncogenic events.
And so, autophagy is required for some steps of the immunosurveillance process.
And it is exactly this process that makes cancer therapies efficient.
So, in contrast to the official dogma that has been en vogue for several decades, chemotherapy
is not just killing the cancer cells as if we used an antibiotic that specifically paralyzes
the metabolism of bacteria.
No.
It is true that chemotherapy induces cancer cell death, but the important point is that
chemotherapy must provoke this cell death in a way that it later leads to an immune
response.
And so, if you have a long-term effect of chemotherapy, for years or decades, that continues
beyond removal of the drug, it is due to an anti-cancer immune response.
And so, since this is so important, the capacity of the chemotherapeutic agent to induce autophagy
is actually required for the long-term efficacy of the treatment.
[Rhonda]: I did not know that.
I had no idea that the induction of autophagy would stimulate the immune system through
this extracellular ATP mechanism.