Re: omega 3 (Otto Warburg had it wrong?)

[Guest guest]

Warburg studied cells in isolation - in vitro rather than in vivo. Recent

research (below) appears to indicate that the ketogenic diet, for instance,

may not be effective in cancers that co-opt fibroblast cells (connective

tissue cells). From my reading it is the fibroblasts that experience the

Warburg Effect, and the cancer cells that propagate this environment. Cancer

cells are not necessarily anaerobic. The mention of angiogenesis inhibitors

as driving cancer growth is particularly interesting to me. Tell me if I

have this-all wrong.

The Autophagic Tumor Stroma Model of Cancer Metabolism

'The Autophagic Tumor Stroma Model of Cancer Metabolism' was first proposed

by Dr. P. nti and colleagues (Drs. Sotgia, ez-Outschoorn,

and Pavlides, among others) in series of 5 papers published in the journal

Cell Cycle.

In these elegant studies, these pioneering researchers show that epithelial

cancer cells use oxidative stress as a " weapon " to extract recycled

nutrients from adjacent stromal fibroblasts (i.e., connective tissue cells).

Oxidative stress in cancer associated fibroblasts then forces these cells to

eat themselves, by a process called " autophagy " or " self-cannibalism " . The

resulting recycled nutrients, derived from catabolism in the tumor stroma,

are then used to power the anabolic growth of cancer cells. Thus, cancer is

a disease of " energy imbalance " , resulting from the vectorial and unilateral

transfer of energy-rich nutrients from the tumor stroma to cancer cells. (This

explains the phenomenon of cancer-associated cachexia (systemic wasting), in

which patients with advanced cancer cannot maintain their normal body weight).

Oxidative stress in cancer associated fibroblasts also has other

consequences. The amplification of ROS (reactive oxygen species) production

feeds back upon the epithelial cancer cells, inducing DNA damage

(double-strand breaks) and aneuploidy (abnormal chromosome number), which

are characteristic of genomic instability. Thus, ROS production in the

stroma fuels cancer cell evolution via a process of random mutagenesis.

Finally, the recycled nutrients produced by autophagy in stromal cells

provide a steady-stream of energy-rich metabolites (chemical building

blocks) to cancer cells, inducing mitochondrial biogenesis, and protecting

these " well-fed " cancer cells against apoptosis.

Thus, cancer cells induce oxidative stress in adjacent fibroblasts, 1) to

generate recycled nutrients via autophagy, 2) to mutagenize themselves and

evolve, and 3) to protect themselves against cell death (apoptosis).

This new model has important implications for both the diagnosis and

treatment of cancer patients. For example, breast cancer patients with

increased stromal autophagy (marked by a loss of stromal Cav-1), are more

likely to undergo early tumor recurrence, lymph-node (LN) metastasis, and

show drug-resistance. Conversely, breast cancer patients with little or no

stromal autophagy (marked by high stromal Cav-1 levels), have a good

clinical outcome. Thus, the use of stromal Cav-1 as a biomarker can identify

high-risk cancer patients at diagnosis, for appropriate treatment

stratification.

Dr. nti and colleagues also observed that epithelial cancer cells use

oxidative mitochondrial metabolism to " fuel " tumor growth and metastasis. In

support of this notion, two high energy-rich metabolites (ketones and

L-lactate) which fuel the mitochondrial TCA cycle, dramatically promote

tumor growth and metastasis, without an increase in tumor angiogenesis.

The " Autophagic Tumor Stroma Model of Cancer " also explains why angiogenesis

inhibitors don't work, and instead induce lethal tumor recurrence, and

metastasis. This is because angiogenesis inhibitors drive " hypoxia " in the

tumor stromal micro-environment. Hypoxia, in turn, drives oxidative stress

and autophagy. These are exactly the conditions that are necessary for the

tumor to prosper, due to the increased stromal production of recycled

nutrients via autophagy. Stromal autophagy, then promotes tumor growth and

metastasis, via the availability of recycled nutrients to fuel mitochondrial

metabolism in cancer cells. Furthermore, ketones are the ideal fuel to be

used during hypoxia, as they burn more efficiently and require less oxygen,

to drive the production of ATP via oxidative mitochondrial metabolism.

Thus, these new findings reverse 85 years of cancer research dogma regarding

tumor metabolism.

Previously, it was thought that cancer cells have defective mitochondria, and

undergo aerobic glycolysis ( " the Warburg

effect). Importantly, nti and colleagues now show that stromal

fibroblasts are undergoing the Warburg effect, due to mitophagy (the

autophagic destruction of mitochondria). Thus, the Warburg effect occurs in

fibroblasts, and not in cancer cells---just the opposite of what most cancer

researchers have argued over the last 85 years.

Dr. nti and colleagues have termed this new idea " The Reverse Warburg

Effect " , to distinguish it from the conventional " Warburg Effect " , which was

thought to take place in cancer cells.

Thus, based on these key observations, and since most cancer researchers

have used isolated tumor cells (in the absence of a living stromal

micro-environment) for their studies, many new experiments will have to be

performed in which cancer cells are co-cultured with fibroblasts. This will

allow us to finally understand how " Cancer Metabolism " really works, in a

compartment-specific manner.

[edit] References

For Reference, please see the following related Open Access articles:

1. Pavlides et al., 2010: The autophagic tumor stroma model of cancer: Role

of oxidative stress and ketone production in fuelling tumor cell metabolism

http://www.landesbioscience.com/journals/cc/article/12721/

2. Bonuccelli et al., 2010: Ketones and lactate " fuel " tumor growth and

metastasis: Evidence that epithelial cancer cells use oxidative

mitochondrial metabolism

http://www.landesbioscience.com/journals/cc/article/12731/

3. ez-Outschoorn et al., 2010: Autophagy in cancer associated

fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction

and NFkB activation in the tumor stromal microenvironment

http://www.landesbioscience.com/journals/cc/article/12928/

4. Chiavarina et al., 2010: HIF1-alpha functions as a tumor promoter in

cancer associated fibroblasts, and as a tumor suppressor in breast cancer

cells: Autophagy drives compartment-specific oncogenesis

http://www.landesbioscience.com/journals/cc/article/12908/

5. ez-Outschoorn et al., 2010: Oxidative stress in cancer associated

fibroblasts drives tumor-stroma co-evolution: A new paradigm for

understanding tumor metabolism, the field effect and genomic instability in

cancer cells http://www.landesbioscience.com/journals/cc/article/12553/

6. Witkiewicz et al., 2010: Loss of stromal caveolin-1 expression predicts

poor clinical outcome in triple negative and basal-like breast cancers

http://www.landesbioscience.com/journals/cbt/article/11983/

7. nti et al., 2010: Understanding the " lethal " drivers of tumor-stroma

co-evolution: Emerging role(s) for hypoxia, oxidative stress, and

autophagy/mitophagy in the tumor micro-environment

http://www.landesbioscience.com/journals/cbt/article/13370/

8. Sloan et al., 2009: Stromal cell expression of caveolin-1 predicts

outcome in breast cancer.

http://ajp.amjpathol.org/cgi/content/full/174/6/2035

9. Ghajar CM et al., 2009: Quis custodiet ipsos custodies: who watches the

watchmen? http://ajp.amjpathol.org/cgi/content/full/174/6/1996

10. Witkiewicz et al., 2009: An Absence of Stromal Caveolin-1 Expression

Predicts Early Tumor Recurrence and Poor Clinical Outcome in Human Breast

Cancers http://ajp.amjpathol.org/cgi/content/full/174/6/2023

[edit] External links

http://www.landesbioscience.com/journals/cc/article/12721/

http://www.landesbioscience.com/journals/cc/article/12731/

http://www.landesbioscience.com/journals/cc/article/12928/

http://www.landesbioscience.com/journals/cc/article/12908

http://www.landesbioscience.com/journals/cc/article/12553/

http://www.landesbioscience.com/journals/cbt/article/11983/

http://www.landesbioscience.com/journals/cbt/article/13370/

http://ajp.amjpathol.org/cgi/content/full/174/6/2035

http://ajp.amjpathol.org/cgi/content/full/174/6/1996

http://ajp.amjpathol.org/cgi/content/full/174/6/2023

http://www.jefferson.edu/cancerbiology/faculty_profile.cfm?key=mpl001

[Guest guest]

Amazing reads... thanks so much!

mario

[Guest guest]

Did I hear Theory....Dr Warbug was never wrong...and has never been proven

wrong..This is only theory....