PCa Heterogenity and cellular senescence - new info on the nature of 'The Beast"

[cujoe]

I have recently posted several papers that point to the wide range of cellular diversity in the development of PCa – even within the prostate and before it becomes metastatic. The following research papers add to the building evidence of wide heterogeneity of PCa and the development of dormant cancer cells in response to various micro-environmental conditions and/or treatment-induced responses. Some portion of these cells eventually become active and leads to treatment resistance, metastatic disease, and worse.

The first paper is a pre-print paper about the use of MRI to evaluate PCa risk prior to treatment of the prostate. The other two are by the same authors and provide an overview of the evolutionary basis for the sort of cellular dormancy that occurs in PCa and other cancers. This excerpt from the Discussion Section of the paper # 2 (pre-print) summarizes the issue for us PCa patients (Note: CSC = Cancer Stem Cell, PACC = PolyAneuploid Cancer Cell):

Discussion

The major cause of death related to PCa is the development of therapy resistant metastatic disease. The possible mechanisms of therapy resistance in PCa have been broadly investigated with multiple candidates such as SOX2 activation, MYC and RAS co-activation, and ERG gene rearrangements 45–47. However, the PACC state may represent an inclusive and unifying explanation for therapy resistance mechanisms that is under-recognized. This cell state is induced by the tumor microenvironment or therapeutic stress, can exist for an extended period of time, and can act as a CSC by undergoing depolyploidization and repopulating the tumor cell population when stress is relieved. In order to systematically study this phenomenon, one needs to go back to the fundamental approach to tumor pathogenesis: cell morphology.

PACCs have two defining characteristics: polyploidy and relatively large size. Polyploidy does not necessarily mean “multi-nucleation” and can be pronounced as a single large nucleus; however, multi-nucleated cells are often polyploid. Because of the increased genomic content, polyploid cells are physically larger than the neighboring tumor cells 12. The presence of PACCs has been shown to be associated with worse prognosis, higher tumor grade, poor differentiation, and advanced disease stage in various tumor types including PCa 30,32,34,36,37,40. There is also evidence in castration-resistant PCa that PACCs drive resistance to taxane-based chemotherapy48.

The full research papers can be found here:

1. Background prostate tissue is quantitatively abnormal on MRI in patients with clinically significant prostate cancer - MedRXiv - this version posted October 13, 2022

medrxiv.org/content/10.1101...

2. Presence of cells in the polyaneuploid cancer cell (PACC) state predicts risk of recurrence in prostate cancer – MedRXiv - posted September 20, 2022

medrxiv.org/content/10.1101...

3. Polyaneuploid Cancer Cell Dormancy: Lessons From Evolutionary Phyla - Frontiers in Ecological Evolution, 07 July 2021, Sec. Behavioral and Evolutionary Ecology

frontiersin.org/articles/10...

It is fast becoming clear that early treatment is better that waiting too late. As one who got to treatment too late for a curative outcome (Thanks, Doc), I believe the up-front diagnostics should be WAY more rigorous than it is now - in order to ID those patients who will likely progress from those with indolent, organ-confined disease that will most likely die with not from PCa. It seem that the tools to do that are now available, but not being used.

Paz - Captain K9

PS For those who want a deeper dive into cancer and evolutionary theory, this Frontiers In (Ecology and Evolution) has several other articles that may be of interest:

From Ecology to Cancer Biology and Back Again - Frontiers In Ecology and Evolution:

frontiersin.org/research-to...

[MateoBeach]

The Frontiers in Ecology article on PACCs is extremely interesting. With comparison of “dormancy” in treatment emergent PACCs and cancer stem cells, to quiescence and other mechanisms for stress survival. Also implications for cell cycle arrest mechanisms that are recognized in various cancer treatments ( including chemotherapy and hormonal therapies). Might actually contribute to cancer survival. OMG!

What was surprisingly absent from the discussion was the other quiescent (non replicating) state of cellular senescence. These cells survive like zombies, not replicating but continuing to promote cancer survival and progression via SASP (Senescence Associated Secretory Phenotype). I have posted about this before. Cancer treatments can and do cause some cells to enter senescence. So does aging for that matter.

How do we get them to die? Apoptosis is the programmed cellular solution. And we do have therapeutics called senolytics that promote this process of clearing senescent cells. These have not been tested clinically nor even pre clinically in Prostate cancer, to my knowledge. However, two of the most widely tested and effective senolytics are natural plant derived and recognized as safe. These are Quercetin and Fisetin. Quercetin has most often been tested combined with the prescription medication Dasatinib, so there are possible risks from that. Typically only used occasionally for a few days and not continuously. 1500 mg Quercetin and 100 mg Dasatinib per day for 3 days only. Fisetin has shown efficacy used alone at 1000-1500 mg/day. Again only occasional use reduces population of senescent fibroblasts. Use for cancer treatment-induced senescent cells is theoretical and not proven. But downside to a few days of Quercetin and Fisetin appears to be small to nil.

Thanks for this post and links, K-9 Cujoe. I will be investigating PACCs further to try and learn more. Pablito (aka Whitefeather)

PS: as we learned in “Transformers”, the metabolic plasticity of cancer also permits the reverse of the Warburg Effect. It is a two way street of metabolic adaptability to conditions and opportunities. Nasty smart disease.

[jdm3 in reply to MateoBeach]

Interesting stuff. Do you have a recommendation for the Fisetin? Most are 100 to 500 mg though I do see some higher doses. Some even with quercetin.

[cujoe in reply to jdm3]

SproutMaster,

While not endorsing either product *, LEF has a form of Fisetin (Bio-Fisetin) that combines a tiny amount of fisetin (8 mg) with an extract from fenugreek seeds. The claim is for 25 x absorption, which if true would be equal to 200 mg of "straight" fisetin? It seems one could just take some fenugreek caps along with straight fisetin and get similar/better results? LEF also has a combination supplement, Senolytic Activator that combines their bio-fisetin and their similar bio-quercetin with several other extracts. No idea if this is an effective combo.

I've not seen specific recommendations from research that would suggest an optimum dosage for most of the standard senolytic supplements. As commented earlier on this forum, while initially enthusiastic about senolytics, I became cautious due to the possibility that what prolongs healthy cells might also prolong cancerous ones. Even David Sinclair admitted in a RR podcast that the jury was still out on that issue re: the various Sirtuins - and that more research was needed. I definitely will stay away from the NAD+ supplements until some research on cancer patients has been done. (As that is likely not a high priority, I don't expect any research to be forthcoming.)

* I currently use either the Vitacost or Dr's Best Fisiten (both 100 mg) on a somewhat random schedule, usually taken with pterostilbene, resveratrol and quercetin - and on occasion with some other anti-inflammatory supps. I also try to take these along with a smoothie that includes a source food for each; i.e., blueberries for pterostilbene, strawberries for fisetin, apples for quercetin, and cacoa for resveratrol - to capture any synergies of the source food.

Hope all is well in the Northern Latitudes. Will PM with an account of my travels later today/tonight. Keep It Safe/Well. Ciao - K9

[cujoe in reply to MateoBeach]

When I finally got around to my mail from my 3 weeks of travel, I found that LEF's November Mag was focused on Senescence and Senolytics. The content is light, but it has a very condensed piece taken from a Nature Medicine Review article by longevity researchers at Mayo Clinic; i.e., Dr. James Kirkland and team. The Nature article is an excellent overview of senescenece/senolytics and the current state of research. The full Nature Medicine article is linked below. (Noteworthy for those of us looking for real evidence of efficacy is the status of senolytic CT's in Table 1):

Cellular senescence and senolytics: the path to the clinic - Nature/Nature Medicine - Review Article - Published: 11 August 2022

nature.com/articles/s41591-...

MB, I left my eReader in AZ, so my completion of Nick Lane's metabolic trilogy will have to wait for it to find a way back to me. Have you made your seasonal move to South of the Border yet? Safe travels either way. Paz - K9

[Scout4answers in reply to MateoBeach]

But downside to a few days of Quercetin and Fisetin appears to be small to nil.

Do you think these should be used daily or intermittently ?

[cujoe in reply to Scout4answers]

Scout - Not to answer for MB, but the following from the Nature Medicine Review Article linked above seems to provide some guidance:

With senolytics, intermittent administration appears to be as effective as continuous treatment for attenuating senescent cell burden21. This intermittent ‘hit-and-run’ strategy of senolytic administration could serve to reduce side effects of agents such as D, which generally appear after weeks to months of continuous administration118,119. In this regard, the advantages of D, Q or F over some other senolytics are their brief half-lives (4, 11 or 3–4 h, respectively, in humans) and rapid elimination.

Note: D=Dasatinib (4 hr half-life), Q=quercetin (11 hr half-life), & F=Fisetin (3-4 hr half-life)

Maybe a case where a short half-life is a plus? (esp. for anyone who can manage to get an off-label script for Dasatinb/Sprycel.)

Be Well - ciao, k9

[MateoBeach in reply to Scout4answers]

exactly as cujoe summarized. While I take several phytochemicals daily that have pretty good evidence for benefit, for both longevity protections and possible PC progression protections. (Not meaning APC treatments.) the ones I take include Quercetin 500mg, Fisetin 400mg, as well as Curcumin, Resveratrol, and Sulforaphane.

But I only do a three day higher dose cycle for possible senolytic benefits about once every two or three months. At those times I increase Quercetin to 1500mg, Fisetin to 800 mg and add Dasatinib 100 mg. Three days only. It is just what I personally have chosen to do now within my overall regimen for healthier living and countering “the beast”. That is not all just about prostate cancer, but protecting and maximizing the “soma “, my aging and precious, but not-all-cancerous body. 💪💕😀

[MateoBeach]

K-9, that is an excellent updated review of senescence and senolytics. Enjoyed reading it on the flight down from Oregon to Los Cabos yesterday. Differential responsiveness of various types of senescent cells to specific senolytics adds considerable uncertainty if D + Q or F will be effective for treatment emergent PC SCs and SASPs. Combo more promising until we know. At least helpful for aging related senescent fibroblasts arising from multiple degenerative mechanisms. S & W and happy. MB

[MateoBeach]

Cujoe my fierce amigo, so much enjoy that issue of Frontiers with many articles I have not yet read. One that drew me immediately is the one on epigenetic mechanisms. While this is still incompletely understood, it will remain very important for all of the health aspects we are concerned with. Probably too much for the typical HU APC or FPC reader, but not for your keen (keening) mind. It discusses how fasting, ketogenic diet periods and heat exposure can modify epigenetic factors to make diverse cellular populations more accessible to “extinction” treatments. It is mostly theoretical but sets the stage for deeper understanding of epigenetic controls through HDACs (including Sirtuins) and longer term or permanent epigenetic modifications via host one methylations and DNA methylations.

Histone acetylations and micro-RNA effects seemingly neglected. Still a good overview and evidence for dietary and heat exposures to help modulate epigenetic s positively. What do you think?

The dog-walker

frontiersin.org/articles/10...

[MateoBeach in reply to MateoBeach]

that’s histone methylations. Damn spell correct.

[cujoe in reply to MateoBeach]

Never mind the spelling, doc. Most of us readin hear r way under wadder wid da content.

In a more serious context, there is quite a bit of research on the metabolic benefits of heat/cold temps and breathing. Wim Hof is an interesting source for info on both temps and breathing techniques and a true character to boot. His feats in cold water swimming are super-human.

wimhofmethod.com/

wimhofmethod.com/news

Fill that Cabo bathtub with ice, relax in style, and then do some Wim Hof breathing. The perfect way to get jump-started on your winter in paradise. Ciao - K9 terror

[MateoBeach]

Tanks fer yer werds K-dog. I can only jump in the ice waters if gettin’ a shot duk, or if after a boiling’ dunk furst. As fer breathin seems a good idee. Read that book. And of course am a yoga teacher too. Teknikaly, any ways.

[cujoe in reply to MateoBeach]

Seams we speek da shame langwige. I do the Wim Hof breathing routine every so often when I first wake up in the morning. It is pretty invigorating.

[MateoBeach]

Kewl K-dog

[NPfisherman]

K9 Public Enemy #1,

You and MB would fit in well here in the WV....lol.. Communication skills indeed...

Interesting reading on cancer evolution and senescence. As the knowledge increases, new targets are found that may push us to the chronic disease state goal, and then....cure. Keep reading and posting. I am sure Nalakrats would have enjoyed this information and had commentary. He should make the switch and join..

Fish