Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Nathan Traller shared this article on face book
Excellent article

Thank you Nathan!

The article is written by a doctor and I placed this link in medical on the forum as it is just that . Medically descriptive to ASPS.

https://breelynwilkymd.com/2016/04/05/t ... o-go-asps/

Clinical trial in Miami
Contact information:
Breelyn Wilky, MD, University of Miami
Phone: 305-243-1287
e-mail: b.wilky@med.miami.edu


http://www.cureasps.org/new-asps-clinic ... -sarcomas/



Nathan's families recent link
Nathalie recently passed away after a courageous battle fought ,from ASPS

http://www.cureasps.org/forum/viewtopic ... t=Nathalie

Great Article..gives hope to a lot of people. Still a lot has to be done but good to know that someone is doing something.

A lot of research needs to be done on ASPS, especially on people which are NED and try to figure out how their body (immune system) works

I just wonder regarding the lactic acid. Is it forbidden to do sports? I'm very active on that part, I go jogging regularly, uphill cycling etc.

Martin - I was also thinking about the interplay here - lactic acid, sports and if the overproduction of the lactic acid increases the aggressiveness of the ASPS. Ivan is very active in sports. There are benefits of doing sports that may decrease his risks so how to balance it I do not know, besides his ASPS aggressiveness does not appear to be changing depends on his sports activities - the mets are slowly growing at the constant rate. I do not see a cause and effect connection in his case, but I am sure that sport brought lots of benefits to his successful recovery from the multiple surgeries and ablation and the ability to have these and to retain his pulmonary function. Person needs strength to survive ASPS and all the treatments that are needed. The question if the sports and physical activities overall increase the survival for the patient with metastatic or non-metastatic cancer itself remains to be open and there is no definite answer to it, but since 10% of the cancer patients die from the treatment related complications, the physical strength is needed and also improves the quality of life.

I completely agree. Probably there are much more benefits. Anyhow when you are doing it regularly guess your strength increases and you do not overload and put your body in a condition to generate so much lactic acid.

Hey Martin and Olga

Just a thought
Measuring lactate levels and establishing or assessing levels to body mass? could be our bloodwork protocol?

I know that blood levels of lactate are suggested . Not sure of the norm needed to not create acidiosis and consequently a lactate emergencey metabolisium useage.

We are a group of Dx'd folks know to be compromised and studies suggest that our sarcoma uses lactate which to my understanding isn't always the case with many cancers/sarcomas? Ie brain tumors?
Hoping someone with more medical knowledge can contribute

Love to all

Carcinogenesis vol.35 no.3 pp.515–527, 2014
doi:10.1093/carcin/bgt480
Advance Access publication December 16, 2013
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium,
provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Review
Cancer as a metabolic disease: implications for novel therapeutics

Metabolics of cancer

Emerging evidence indicates that cancer is primarily a metabolic
disease involving disturbances in energy production through
respiration and fermentation. The genomic instability observed
in tumor cells and all other recognized hallmarks of cancer are
considered downstream epiphenomena of the initial disturbance
of cellular energy metabolism. The disturbances in tumor cell
energy metabolism can be linked to abnormalities in the structure
and function of the mitochondria. When viewed as a mitochondrial
metabolic disease, the evolutionary theory of Lamarck
can better explain cancer progression than can the evolutionary
theory of Darwin. Cancer growth and progression can be managed
following a whole body transition from fermentable metabolites,
primarily glucose and glutamine, to respiratory metabolites,
primarily ketone bodies. As each individual is a unique metabolic
entity, personalization of metabolic therapy as a broad-based
cancer treatment strategy will require fine-tuning to match the
therapy to an individual’s unique physiology.




(Ie old theory " Warburg’s central theory ")

Influence of unnatural growth environment on cellular energy
metabolism
Much of the evidence arguing against Warburg’s central theory that
respiratory insufficiency is the origin of the aerobic fermentation
seen in cancer cells (Warburg effect) was derived from investigations
of tumor cells grown in vitro (64,78,79,108–110).

http://www.ncbi.nlm.nih.gov/pmc/article ... bgt480.pdf

So Lactate, in my humble opinon ,is the end results of a successful or unsuccesful metabolic days end . So very important for a cancer patient
Especially us guys

Night Love again to all

Reading on lactate and its high levels being one of the causes of chemo/radio resistance. As Ewings sarcoma is a bone sarcoma, the studies have focused on those folks, with their high levels of lactate from bone metastasis . High levels equate to poor survival . Would be interested to hear some opinions.

Pretreatment Serum Lactate Dehydrogenase Predicting Metastatic Spread in Ewing's Sarcoma
http://annals.org/aim/article/689661/pr ... rcomaphone

Prognostic significance of serum lactate dehydrogenase levels in Ewing's sarcoma: A meta‑analysis

https://www.spandidos-publications.com/ ... o-0-0-1066

The useage of radiation and or chemotherapies during these times of high lactate , have shown low results of success. Been linked to radio /chemo resistance in some cancers.

Lactate promotes resistance to glucose starvation via upregulation of Bcl-2 mediated by mTOR activation

https://www.spandidos-publications.com/or/33/2/875

Lactate promotes resistance to glucose starvation via upregulation of Bcl-2 mediated by mTOR activation

https://www.spandidos-publications.com/or/33/2/875


Abstract

Solid tumors grow faster and need more glucose than normal tissue; however, due to poor angiogenesis and excessive growth, tumors remote from blood vessels are always under glucose starvation. Even so, cancer cells remain alive in vivo. Thus, making cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. Tumors that obtain sufficient glucose generate a large amount of lactate. Therefore, we proposed that lactate, a tumor microenvironment factor, may allow cancer cells to develop resistance to glucose starvation-induced death. We cultured cancer cells in no-glucose medium and added lactate to the medium. During the experiment, lactate helped cancer cells to escape from glucose starvation-induced cell death, without using lactate as an energy substrate, resulting in activation of Akt through PI3K. Akt activation plays a central role in cell growth through the activation of mammalian target of rapamycin (mTOR). Alteration of the PI3K/Akt/mTOR signaling pathway by inhibiting apoptosis induced specific upregulation of B-cell lymphoma 2 (Bcl-2) through translational control. In conclusion, this study showed that lactate rescues cancer cells from glucose starvation-induced cell death through regulation of the PI3K/Akt/mTOR/Bcl-2 signaling pathway. These data suggest that lactate is an important determinant of the sensitivity of tumors to glucose starvation, and reducing lactate or inhibiting the PI3K/Akt/mTOR/Bcl-2 signaling pathway may influence the response of cancers to glucose starvation.



Discussion

Reprogramming energy metabolism is a hallmark of cancer (5). Warburg (4) first observed that even in cases with an adequate oxygen supply, tumors still preferred to utilize glucose via glycolysis. Compared with oxidative phosphorylation, glycolysis is a low efficiency method of energy production; therefore, compared with normal tissue, tumors often require more glucose. The clinical diagnosis of cancer by PET with a radiolabeled analog of glucose (FDG) as a reporter, a widely used method, is possible as tumor cells have increased glucose uptake (15). These changes in tumor metabolic patterns, increased glucose uptake and glycolysis as the main production method, eventually lead to the accumulation of lactate, the end product of glycolysis, in tumors. Several studies have reported increased lactate levels within tumors, which reflects the high metastasis rate and poor prognosis in human cervical cancers (16), human head and neck cancers (17), human rectal adenocarcinomas (18), human hepatocellular carcinoma (19) and non-small cell lung cancers (20). Some studies have suggested that lactate could be used as an energy source by oxidative phosphorylation to generate ATP (21,22). Lactate can also be used as a signaling molecule in tumor cells (23). Lactate can produce the promotion of VEGF in wound healing (24), and lactate is also sufficient to instigate signals for angiogenesis (25).

In solid tumors, along with the rapid growth of the tumor, the development of blood vessels within is incomplete, which leads to certain areas of the tumor to suffer glucose deficit. In blood-rich regions, aerobic glycolysis consumes a large amount of glucose to produce lactate, whereas the lactate in the blood-poor regions of tumor cells plays an important role. In the present study, in the absence of glucose, added lactate in culture significantly prolonged the survival of A549 cells in a concentration-dependent manner. This result was consistent with those of the Wu et al (26). Subsequent experiments in different cell lines confirmed the role of lactate. Some studies reported that lactate could be used as an energy substrate to produce ATP by tumor cells through oxidative phosphorylation; we determined whether under no glucose conditions, lactate could be used as an energy substrate. The results showed no significant changes in oxygen consumption and or any lactate consumption. Thus, under glucose-free conditions, lactate is not an energy substrate. We also ruled out an acidic environment in glucose-free conditions as having any influence on maintaining tumor cell growth.

Notably, lactate had different effects on different cell lines, allowing cell lines to be divided into sensitive and insensitive lactate groups. We compared the genetic backgrounds of the five cell lines and found that the cell lines insensitive to lactate lacked PTEN function. Insulin-mediated stimulation of growth confirmed the activation of the Akt signaling pathway in the insensitive cell lines. Therefore, to further explore the mechanism of lactate, we focused on the Akt signaling pathway. Akt signaling pathway is an important signaling pathway in tumor cell survival and development. It is activated by upstream signaling molecules, such as growth factors, and is then further regulated by downstream molecules to participate in the occurrence and development of tumors (14). The activation of the PI3K/Akt pathway could help tumor resistance under dietary deficient conditions (27). Western blotting showed that lactate activated Akt via the rapid phosphorylation at Thr308 and Ser473 mediated by PI3K. Lactate can be used as a signaling molecule in the regulation of certain signaling pathways. For example, lactate was found to upregulate the transcription of 673 genes in L6 cells and was further involved in mitochondrial biogenesis (28). In tumors, lactate, in the presence of oxygen, stimulated the expression of HIF-1α and upregulated various hypoxia-inducible dependent genes (29). Lactate could increase TLR4 signaling and NF-κB pathway-mediated gene transcription in macrophages (30). Lactate increased the level of TGF-β2 in glioma (31). Interestingly, further experiments demonstrated that lactate helped tumor cell survival in glucose-free conditions through activation of Akt by phosphorylation.

Apoptosis tends to occur when cells are under metabolic stress because of lack of glucose. We found significant apoptosis of A549 cells under glucose-free environment conditions, and the addition of lactate prevented this apoptosis. The Bcl-2 family of anti-apoptotic proteins are key regulators of cell apoptosis (32). We found that lactate increased the expression of Bcl-2, and downregulation of Bcl-2 protein expression using an siRNA reduced the resistance to apoptosis induced by lactate in glucose-free conditions.

The PI3K/Akt signaling pathway plays a key role in inhibiting apoptosis, thereby promoting cell proliferation. The activation of Akt can act directly on apoptosis-related proteins to regulate apoptosis. Activation of Akt induces phosphorylation of caspase-9 at the Ser196 site, which inhibits apoptosis (33). The PI3K/Akt signaling pathway can directly or indirectly affect the functions of transcription factors to regulate cell survival. Akt can inhibit the enzyme IκBα that phosphorylates NF-κB, whereas unphosphorylated NF-κB in the nucleus regulates anti-apoptotic gene transcription (34). Akt can prevent the mitochondrial release of cytochrome c and apoptosis-inducing factors, contributing to apoptosis resistance (35). In the present study, we confirmed that lactate acts via the PI3K/Akt pathway to regulate Bcl-2, inhibiting apoptosis caused by the lack of glucose.

In conclusion, lactate helps tumor cells to resist apoptosis caused by glucose starvation. Lactate, through PI3K, activates Akt by phosphorylation, which activates mTOR and further increases the expression of anti-apoptotic protein Bcl-2. This study indicates that treatments targeting lactate could more effectively inhibit the survival of tumors.

Researchers are working hard to understand the mechanism responsible for oncogenesis, the process through which normal cells become cancerous ones. A new study focuses on lactate - a molecule produced during intense exercise - and explains its role in cancer cell formation.
New research, published in the journal Carcinogenesis, analyzes the role of lactate in oncogenesis.

Lactate is a byproduct of the chemical process known as glycolysis - the breaking down of sugar, or glucose, into smaller molecules with the purpose of producing energy. During intense physical activity, lactate accumulates in the tissue and blood, which can sometimes lead to poorer physical performance and muscle stiffness.

At the beginning of the 20th century, German scientist Otto Warburg noticed that cancer cells consume a lot more glucose than normal cells. The so-called Warburg effect refers to the fact that cancer cells undergo more glycolysis and produce more lactate compared with normal cells.

The new research - led by Inigo San Millan, director of the Sports Performance Department and physiology laboratory at the University of Colorado-Boulder's Sports Medicine and Performance Center - set out to understand why the Warburg effect happens. Since Warburg's time, the focus in cancer research has shifted from cell metabolism to genetics, but the new paper hopes to put lactate back at the center of cancer research.


Studying the role of lactate in oncogenesis

San Millan and colleagues suggest that the molecule is "the only metabolic compound involved and necessary" in the five stages that follow on from carcinogenesis.

The study examines the role of lactate in angiogenesis (the process by which new blood vessels form inside the tumors), immune escape (the cancer cells' ability to elude the body's immune response), and cell migration, as well as in metastasis and self-sufficient metabolism.

The paper explains how in metastasis, lactate helps to create an acidic microenvironment outside the cancer cell, which supports the spread of cancer cells.

Finally, the study also explores the link between lactate and genetic components. The researchers hypothesize that a triad of transcription factors commonly found in most cancers - HIF-1, cMYC, and p53 - also triggers and perpetuates lactate deregulation.

'To stop cancer you have to stop lactate'

The crucial role of lactate in cancer cell formation may explain why people who exercise regularly are at a lower risk of developing cancer. In athletes and those who work out, the body is trained to efficiently turn lactate into an energy source for the body, thus stopping it from accumulating in excess.

Based on their findings, the researchers speculate that a sedentary lifestyle, combined with too much sugar in our diets, may lead to an excessive accumulation of lactate, thus setting the stage for cancer.

"With this paper, we open a whole new door for understanding cancer, showing for the first time that lactate is not only present, but mandatory for every step in its development."
Inigo San Millan
In the near future, San Millan will collaborate with the University of Colorado Hospital to study the effect of tailored exercise programs on cancer patients. The researcher is already studying breast cancer cell lines.

San Millan hopes that, eventually, his research will help to develop drugs that stop the lactate from accumulating. "We hope to sound the alarm for the research community that to stop cancer you have to stop lactate," he says. "There are many ways to do that," such as by targeting monocarboxylate transporters, which ferry lactate from cell to cell.





https://www.google.com/amp/s/www.medica ... amp/316438

Finally, the study also explores the link between lactate and genetic components. The researchers hypothesize that a triad of transcription factors commonly found in most cancers - HIF-1, cMYC, and p53 - also triggers and perpetuates lactate deregulation.

“HIF is a transcription factor that plays an essential role in the cellular response to low oxygen, orchestrating a metabolic switch that allows cells to survive in this environment. In immunity, infected and inflamed tissues are often hypoxic, and HIF helps immune cells adapt.Oct 6, 2020”

“c-Myc is a multifunctional transcription factor which drives the multiple synthetic functions necessary for rapid cell division while at the same time inhibiting expression of genes with antiproliferative functions. Because of its propensity to induce apoptosis, its expression is tightly regulated.”

https://cureasps.org/forum/viewtopic.php?p=16085#p16085

Bump