This is the updated version of Dr. Otto Warburg’s classic “The Metabolism of Tumours.” The updated version is in epub format, which is easier to read on smartphones and tablets. It also includes photos and a brief biography of Dr. Warburg. In his own words: There are prime and secondary causes of diseases. For example, the prime cause of the plague is the plague bacillus, but secondary causes of the plague are filth, rats, and the fleas that transfer the plague bacillus from rats to man. By a prime cause of a disease I mean one that is found in every case of the disease...Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation. All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes. From the standpoint of the physics and chemistry of life this difference between normal and cancer cells is so great that one can scarcely picture a greater difference. Oxygen gas, the donor of energy in plants and animals is dethroned in the cancer cells and replaced by an energy yielding reaction of the lowest living forms, namely, a fermentation of glucose… If a lowered oxygen pressure during cell growth may cause cancer, or, more generally, if any inhibition of respiration during growth may cause cancer, then a next problem is to show why reduced respiration induces cancer. Since we already know that with a lowering of respiration fermentation results, we can re- express our question: Why does cancer result if oxygen-respiration is replaced by fermentation? The early history of life on our planet indicates that life existed on earth before the earth’s atmosphere contained free oxygen gas. The living cells must therefore have been fermenting cells then, and, as fossils show, they were undifferentiated single cells. Only when free oxygen appeared in the atmosphere - some billion years ago - did the higher development of life set in, to produce the plant and animal kingdoms from the fermenting, undifferentiated single cells. What the philosophers of life have called "Evolution créatrice" has been and is therefore the work of oxygen. The reverse process, the dedifferentiation of life, takes place today in greatest amount before our eyes in cancer development, which is another expression for dedifferentiation. To be sure, cancer development takes place even in the presence of free oxygen gas in the atmosphere, but this oxygen may not penetrate in sufficient quantity into the growing body cells, or the respiratory apo-enzymes of the growing body cells may not be saturated with the active groups. In any case, during the cancer development the oxygen-respiration always falls, fermentation appears, and the highly differentiated cells are transformed to fermenting anaerobes, which have lost all their body functions and retain only the now useless property of growth. Thus, when respiration disappears, life does not disappear, but the meaning of life disappears, and what remains are growing machines that destroy the body in which they grow.

Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.

The book addresses controversies related to the origins of cancer and provides solutions to cancer management and prevention. It expands upon Otto Warburg's well-known theory that all cancer is a disease of energy metabolism. However, Warburg did not link his theory to the "hallmarks of cancer" and thus his theory was discredited. This book aims to provide evidence, through case studies, that cancer is primarily a metabolic disease requring metabolic solutions for its management and prevention. Support for this position is derived from critical assessment of current cancer theories. Brain cancer case studies are presented as a proof of principle for metabolic solutions to disease management, but similarities are drawn to other types of cancer, including breast and colon, due to the same cellular mutations that they demonstrate.

Ergebnisse von in vitro-Studien lassen vermuten, dass sich der pH-Wert in einem Tumor auf die Wirksamkeit von Chemo- oder Strahlentherapien auswirken kann. Wie aber sieht die Beziehung zwischen der Tumorentwicklung und dem pH-Wert aus? Können ein niedriger pH-Wert oder ein Sauerstoffmangel die Carcinogenese hemmen? Wo bieten sich therapeutische Ansätze? Anwort auf diese und andere Fragen finden Sie in diesem Band. In interdisziplinärer Weise wurden Beiträge aus der Grundlagenforschung und der klinischen Praxis zusammengetragen.

This textbook presents concise chapters written by internationally respected experts on various important aspects of cancer-associated metabolism, offering a comprehensive overview of the central features of this exciting research field. The discovery that tumor cells display characteristic alterations of metabolic pathways has significantly changed our understanding of cancer: while the first description of tumor-specific changes in cellular energetics was published more than 90 years ago, the causal significance of this observation for the pathogenesis of cancer was only discovered in the post-genome era. The first 10 years of the twenty-first century were characterized by rapid advances in our grasp of the functional role of cancer-specific metabolism as well as the underlying molecular pathways. Various unanticipated interrelations between metabolic alterations and cancer-driving pathways were identified and currently await translation into diagnostic and therapeutic applications. Yet the speed, quantity, and complexity of these new discoveries make it difficult for researchers to keep up to date with the latest developments, an issue this book helps to remedy.

The Optimal Terrain Ten Protocol to Reboot Cellular Health Since the beginning of the twentieth century, cancer rates have increased exponentially--now affecting almost 50 percent of the American population. Conventional treatment continues to rely on chemotherapy, surgery, and radiation to attack cancer cells. Yet research has repeatedly shown that 95 percent of cancer cases are directly linked to diet and lifestyle. The Metabolic Approach to Cancer is the book we have been waiting for--it offers an innovative, metabolic-focused nutrition protocol that actually works. Naturopathic, integrative oncologist and cancer survivor Dr. Nasha Winters and nutrition therapist Jess Higgins Kelley have identified the ten key elements of a person's "terrain" (think of it as a topographical map of our body) that are crucial to preventing and managing cancer. Each of the terrain ten elements--including epigenetics, the microbiome, the immune system, toxin exposures, and blood sugar balance--is illuminated as it relates to the cancer process, then given a heavily researched and tested, non-toxic and metabolic, focused nutrition prescription. The metabolic theory of cancer--that cancer is fueled by high carbohydrate diets, not "bad" genetics--was introduced by Nobel Prize-laureate and scientist Otto Warburg in 1931. It has been largely disregarded by conventional oncology ever since. But this theory is resurging as a result of research showing incredible clinical outcomes when cancer cells are deprived of their primary fuel source (glucose). The ketogenic diet--which relies on the body's production of ketones as fuel--is the centerpiece of The Metabolic Approach to Cancer. Further, Winters and Kelley explain how to harness the anticancer potential of phytonutrients abundant in low-glycemic plant and animal foods to address the 10 hallmarks of cancer--an approach Western medicine does with drug based therapies. Their optimized, genetically-tuned diet shuns grains, legumes, sugar, genetically modified foods, pesticides, and synthetic ingredients while emphasizing whole, wild, local, organic, fermented, heirloom, and low-glycemic foods and herbs. Other components of their approach include harm-reductive herbal therapies like mistletoe (considered the original immunotherapy and common in European cancer care centers) and cannabinoids (which shrink tumors and increase quality of life, yet are illegal in more than half of the United States). Through addressing the ten root causes of cancer and approaching the disease from a nutrition-focused standpoint, we can slow cancer's endemic spread and live optimized lives.

This is book 2 of 5 of the “Understand Cancer” series. It is based on the best-available science. The SECONDARY causes of cancer were discussed in book one. This book continues from book one and discusses the PRIME cause of cancer as discovered by Nobel Prize Laureate Dr. Otto Warburg—considered by many as the founder of modern biochemistry. “There are prime and secondary causes of diseases. For example, the prime cause of the plague is the plague bacillus, but secondary causes of the plague are filth, rats, and the fleas that transfer the plague bacillus from rats to man. By a prime cause of a disease I mean one that is found in every case of the disease...Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation. All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes. From the standpoint of the physics and chemistry of life this difference between normal and cancer cells is so great that one can scarcely picture a greater difference. Oxygen gas, the donor of energy in plants and animals is dethroned in the cancer cells and replaced by an energy yielding reaction of the lowest living forms, namely, a fermentation of glucose.” —Dr. Otto Warburg

Development of an effective anticancer therapeutic necessitates the selection of cancer-related or cancer-specific pathways or molecules that are sensitive to intervention. Several such critical yet sensitive molecular targets have been recognized, and their specific antagonists or inhibitors validated as potential therapeutics in preclinical models. Yet, majority of anticancer principles or therapeutics show limited success in the clinical translation. Thus, the need for the development of an effective therapeutic strategy persists.

“Altered energy metabolism” in cancer is one of the earliest known biochemical phenotypes which dates back to the early 20th century. The German scientist, Otto Warburg and his team (Warburg, Wind, Negelein 1926; Warburg, Wind, Negelein 1927) provided the first evidence that the glucose metabolism of cancer cells diverge from normal cells. This phenomenal discovery on deregulated glucose metabolism or cellular bioenergetics is frequently witnessed in majority of solid malignancies. Currently, the altered glucose metabolism is used in the clinical diagnosis of cancer through positron emission tomography (PET) imaging. Thus, the “deregulated bioenergetics” is a clinically relevant metabolic signature of cancer cells, hence recognized as one of the hallmarks of cancer (Hanahan and Weinberg 2011). Accumulating data unequivocally demonstrate that, besides cellular bioenergetics, cancer metabolism facilitates several cancer-related processes including metastasis, therapeutic resistance and so on. Recent reports also demonstrate the oncogenic regulation of glucose metabolism (e.g. glycolysis) indicating a functional link between neoplastic growth and cancer metabolism. Thus, cancer metabolism, which is already exploited in cancer diagnosis, remains an attractive target for therapeutic intervention as well. The Frontiers in Oncology Research Topic “Cancer Metabolism: Molecular Targeting and Implications for Therapy” emphases on recent advances in our understanding of metabolic reprogramming in cancer, and the recognition of key molecules for therapeutic targeting. Besides, the topic also deliberates the implications of metabolic targeting beyond the energy metabolism of cancer. The research topic integrates a series of reviews, mini-reviews and original research articles to share current perspectives on cancer metabolism, and to stimulate an open forum to discuss potential challenges and future directions of research necessary to develop effective anticancer strategies. Acknowledgment I sincerely thank the Frontiers for providing the opportunity and constant support throughout the process of this research topic and eBook production. I gratefully acknowledge all the authors for their valuable contributions. Finally, I would like to thank my brother, Saravana Kumar, G.K., whose personal sacrifices and unflinching encouragement made my career in science possible. References: Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: The next generation. Cell. 144(5):646-74. Warburg O, Wind F, Negelein E. 1926. Über den stoffwechsel der tumoren in körper. Klinische Wochenschrift. 5:829-32. Warburg O, Wind F, Negelein E. 1927. The metabolism of tumors in the body. J Gen Physiol. 8(6):519-30.

Metabolism of glucose, lipids, amino acids, and nucleotides represents the fundamental capability of host to utilize distinct nutrients and energy to support diverse function of different cell lineages. Cancer cells undergo the Warburg Effect to adapt to the microenvironment composed by stromal cells and immune cells. The crosstalk among cancer cells and immune cells orchestrate tumor progression. In the tumor microenvironment, immune cells also show metabolic reprogramming. For example, naive or memory T cells switch from the oxidation of fatty acids to glycolysis and glutaminolysis after activation; meanwhile massive glucose and glutamine are transported into cells to meet their metabolic demands. Defective glucose or glutamine metabolism impairs the differentiation and expansion of helper T cells. The molecular pathways that control immune cell metabolism and function are intimately linked. Understanding such metabolic reprogramming of immune cells in the tumor microenvironment could offer new directions in manipulation of peripheral immune responses. Recent findings in immune cell metabolism hold the promising possibilities by metabolic manipulation of immune cells towards clinical therapeutics for treating cancer. This Research Topic includes updated findings and views in the metabolism of cancer cells and immune cells in the tumor microenvironment.