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    Tumors aren’t just clumps of cancer cells. Tumors are abnormal “organs” composed of multiple cell types. They are complex tissues that interface with the entire organism. In addition to the actual cancer cells, tumors contain connective tissue cells (also known as fibroblasts), cancer stem cells, adipocytes (fat cells), immune cells, and blood vessels. Apart from the cancer cells, the other components are collectively known as the tumor “stroma” and account for nearly 50% of a tumor’s weight. Cancer cells are like fast-growing “seeds” and the stroma is the fertile “soil.” Furthermore, the seeds (cancer cells) cells can instruct the stroma (soil) to undergo metabolic changes that promote malignancy.
    Cancer is a systemic metabolic disease, likely initiated by DNA damage and activation of oncogenes (cancer-causing genes), and fueled by oxidative stress, inflammation, and hypoxia (low tissue oxygenation). This gives rise to the malignant transformation of normal cells to cancer cells. Oncogenes give the newly formed cancer cells the ability to manipulate and reprogram the metabolism of the tissue microenvironment for their selfish benefit at the expense of the host.
    Oncogenes impart cancer cells with the ability to become predatory and function as “metabolic parasites.” Cancer cells begin producing highly oxidative compounds—also known as reactive oxygen species (ROS)—that activate inflammatory- and hypoxia-signaling molecules in fibroblasts, which together, destroy most of the mitochondria in the once-normal fibroblasts. Once this occurs, they become “enslaved” and turn into cancer-associated fibroblasts (CAFs). With most of their mitochondria destroyed, CAFs lose the ability to produce energy-rich ATP (adenosine triphosphate) via the efficient tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). CAFs are now forced to rely on inefficient aerobic glycolysis (cytoplasmic conversion of glucose to lactate and pyruvate) for their ATP production. To keep this process going, cancer cells produce Fibroblast Growth Factor (FGF) to stimulate the formation of new fibroblasts that will become CAFs.
    After CAFs are forced into glycolysis by the parasitical cancer cells, CAFs undergo self-digestion (autophagy) and are catabolized (broken down) to yield energy-rich lactate and ketones, which are pumped out by their Monocarboxylate Transporter 4 (MCT4) and shuttled to the neighboring cancer cells. The lactate and ketones are then pumped inside the hungry cancer cells by their Monocarboxylate Transporter 1 (MCT1). Once inside, lactate and ketones are efficiently burned in the mitochondria of the cancer cells via the TCA cycle and OXPHOS to yield the enormous amounts of ATP that cancer cells need to fuel their rapid growth (anabolism) and spread (metastasis).
    To further assist cancer, CAFs stimulate the production and activity of mitochondria in cancer cells, upregulate (make more active) MCT1 and MCT 4, promote the growth and spread of cancer independent of angiogenesis (growth of new blood vessels to tumors), inhibit apoptosis (death) of cancer cells by protecting them from the toxic effects of oxidative stress and inflammation in the tumor microenvironment, induce immune suppression and block cancer cells from immune attack, and impart resistance to chemotherapy. The phrase, “No man is an island,” certainly applies to cancer. Cancer cannot do it all on its own. It needs the help of CAFs.
    To effectively starve cancer cells by cutting off their fuel supply, it is not enough to restrict dietary glucose. You must metabolically “uncouple” cancer cells from CAFs to stop the energy transfer from the lactate- and ketone-shuttle. From a therapeutic perspective (more on this later), one must use a combination of repurposed medicines, peptides, and natural compounds to:

    • Revert CAFs back to normal (non-cancer-associated) fibroblasts
    • Downregulate (make less active) oncogenes and upregulate (make more active) cancer-suppressor genes
    • Stimulate DNA-repair mechanisms
    • Decrease reactive oxygen species (ROS) and the resultant oxidative stress
    • Inhibit inflammation-signaling molecules, namely nuclear factor-kappa beta (NF-κβ)
    • Inhibit hypoxia signaling molecules, namely hypoxia-inducible factor-1 alpha (HIF-1α)
    • Block glycolysis in CAFs
    • Downregulate MCT1 in cancer cells and MCT4 in fibroblasts
    • Target the fibrotic activity of CAFs
    • Inhibit fibroblast growth factor (FGF) and connective tissue growth factor (CTGF)
    • Block autophagy in fibroblasts
    • Promote autophagy in cancer cells

    The Reverse Warburg Effect
    In the early 1920s, Dr. Otto Warburg, a Nobel Prize winner, articulated a hypothesis—later called the Warburg effect—to explain the “fundamental basis” of cancer, based on his observations that cancer exhibited a metabolic shift toward aerobic glycolysis. In 1963, Dr. Christian de Duve, another Nobel prize winner, first coined the term autophagy, derived from the Greek words “auto” and “phagy,” literally meaning “self” and “eating.” Fast-forward to today and we see that these two concepts (aerobic glycolysis and autophagy) converge in the tumor stroma.
    To create a lethal tumor microenvironment, cancer cells behave as metabolic “parasites” by inducing oxidative stress, mitochondrial dysfunction, and glycolytic reprogramming in adjacent normal fibroblasts. This true host-parasite relationship transforms fibroblasts into CAFs and forced to digest themselves to produce high-energy nutrients (such as lactate and ketones) to fuel oxidative mitochondrial metabolism in cancer cells and subsequent growth of tumors, without the need for vascularization (blood vessels). Autophagy in the tumor stroma serves as the “battery” to power tumor growth, progression, and metastasis.
    This new “two-compartment” cancer model is called the reverse Warburg effect and it combines two well-established paradigms: aerobic glycolysis and autophagy. In this new paradigm, catabolism (autophagy) of stromal fibroblasts fuels anabolism (growth) of cancer cells. This updated understanding has helped us develop new anticancer strategies designed to uncouple the metabolic parasitic relationship between cancer cells and their associated fibroblasts. Any treatment that targets cancer cells (“seeds”) without also targeting the tumor stroma (“soil”) will likely fail in terms of achieving long-term survival.

    Dr. Daniel Thomas, DO, MS
    Mount Dora, Florida

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