Transcript: Prostate cancer progression

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Last updated:1st May 2025

Published:1st May 2025

Bertrand Tombal, MD, PhD

All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.

So for prostate cancer, like for any other cancer, the first step is the transformation from a normal or precancerous cell into a cancerous cell. So as you may guess, this happened in the prostate first, and usually, it starts with a local growth and this is that local growth that local component of the cancer that you will primarily target with local treatments such as surgery and radiotherapy. Then at some point, the cells get the possibility of being invading, meaning that through the lymphatic or the venous network, it can actually spread out [into] the body. Usually, it is assumed, but it's not necessarily true, that the first landing site will be lymph nodes. First in the pelvis, then going up, although that's not sure, but then it can land in the lymph nodes and develop lymph node metastasis. Then as a third or parallel step, we don't know exactly, it can deposit elsewhere. Historically, it is been shown that the number one landing site for prostate cancer is bone metastasis. When we say bone metastasis, actually, it means that it's gonna go and the bone remodelling niche, you know, where osteoblast and osteoblastic and the prostate cancer cell finds it the perfect environment for growing and that's why bone metastasis are so frequent in prostate cancer. We speak about an osteophilic cancer. It can also deposit in other organs such as the lungs or the liver, but it's usually a late event. What is very important to understand is that not every single cancer cell is capable of that. There are degrees of differentiation that are actually representing different genetic events, which can facilitate that mechanism. What we know in prostate cancer is that we can guess that propension to form metastasis just by the pathology, and that's the discovery of Mr Gleason and that's the genesis of the Gleason score where just looking at the architecture of the prostate cancer, you can have a good guess of how likely it will start this metastatic process. And for instance, a low Gleason score like Gleason 6 that we call low ISUP group or Gleason Group 1 have an extremely low metastatic potential, meaning that they don't even need local treatment.

Nothing will happen. At the opposite of the spectrum, Gleason 8, 9, 10 or ISUP 4 and 5 have a very high metastatic potential. Then where come recurrence? Basically, recurrence may come from different mechanism based on your primary treatment. If your primary treatment was surgery, technically the prostate was removed and you have absolutely no reason to develop recurrence, except that in most patients with high Gleason score, the metastatic process has already initiated. Simply, we don't see it. So the remaining cells will get activated and grow later on. For radiotherapy, you may have the same process, but also, you may have also remnants in the prostate, which are not controlled fully by the radiotherapy. So a two distinct modes of action. The reason why this prostate [cancer] grows in the different organ is extremely complex, but what we know is that in that complex androgens such as testosterone dihydrotestosterone play an important role. They don't necessarily fuel the cancer that, they're not fueling it, they're just maintaining a life and they're kind of a very important survival, survival pathway.

And this is a very old discovery from the forties by Charles Huggins who showed that actually, if you stop the production of testosterone, at that time he did surgical castration, oestrogen. If you stop the production of the testosterone, the cell will shrink and induce apoptosis. So that's why hormonal manipulation either via the lowering of the testosterone or direct blockade of the androgen receptor, which is more recent approach, will basically stop the cancer. And in the case of radiation therapy, probably make it more susceptible to radiation therapy as well. Already, in the forties, Huggins showed that it is extremely, extremely efficient but for a short period of time. There are two theories beside that. The first one is that, at the time of the development, not all the component is dependent of the androgen receptor testosterone axis. And there are other axis such as DNA permutation PTEN/AKT pathways, other survival pathways that are creating what we call androgen receptor independent clones. Or that by actually repressing the androgen receptor pathway, the cells find a way to survive. And these two concepts together explain why in case of aggressive cancer, hormonal manipulation will not be necessary and in absence of testosterone, or under repression of the androgen receptor, the cells may develop survivors and then develop creating the concept of castration-resistant prostate cancer. So that is why we use this terminology of hormone-sensitive and castration-resistant.

Hormone-sensitive means testosterone [is] still there, AR is activated, and there is that high susceptibility to hormonal manipulation. That's why we speak about hormone-sensitive. If you suppress the testosterone or the androgen receptor the cell, some cells die. But it also highlights the fact that the cells may survive in absence of external testosterone or under suppression and that's what we call castration-resistant. That term of castration-resistant is a old term that was used at the time where the primary hormonal manipulation was to lower testosterone. So mimic the effect of a surgical castration In modern days where we use combination of agent that suppress testosterone and block the androgen receptor directly, we may have to redefine that concept of castration-resistant into something like hormonal manipulation resistant prostate cancer. But anyway, this is a term we use all the time and clearly define these two states of the disease. What are the mechanisms involved in that? Once again, I do repeat, there are myriads of mechanisms. Usually, the androgen receptor remains manipulable over the time, but there are many gene modification, some of them being actually addressable by drug like DNA repair abnormalities, AKT/PTEN pathway abnormality, abnormalities in the retinoblastoma gene. So it's a very complex and heterogeneous model, but the good news is that we start to understand it much better and have drugs to interfere it. But sometimes it's not necessary, and we have to imagine new treatment and strategy to directly hit these cells which are not sensitive to hormonal manipulation anymore.

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