Advances in Experimental Medicine and Biology 1311 Anne Le Editor The Heterogeneity of Cancer Metabolism Second Edition Advances in Experimental Medicine and Biology Volume 1311 Series Editors Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS and University of Bordeaux, Pessac Cedex, France Haidong Dong, Departments of Urology and Immunology, Mayo Clinic, Rochester, MN, USA Heinfried H. Radeke, Institute of Pharmacology & Toxicology, Clinic of the Goethe University Frankfurt Main, Frankfurt am Main, Hessen, Germany Nima Rezaei, Research Center for Immunodefciencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Junjie Xiao, Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Science, School of Life Science, Shanghai University, Shanghai, China Advances in Experimental Medicine and Biology provides a platform for scientifc contributions in the main disciplines of the biomedicine and the life sciences. 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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland This book is dedicated to my colleague and mentor, Dr. Arthur J. L. Cooper. Foreword According to the Center for Disease Control (CDC) in 2018, there were 599,274 cancer deaths in the USA; 283,721 were among females and 315,553 were among males (out of an estimated total US population of 328 million in 2018) [1]. Worldwide in 2020 there were an estimated 10.1 million new cases of cancer in males and 5.5 million cancer-related deaths; in females estimated new cases were 9.2 million and 4.4. million deaths [2]. Lung cancer is cur- rently the leading cause of all cancer deaths (25.1% of all cases), but for females breast cancer is currently the leading cause of cancer deaths (15.5%) [2]. According to an April 4th, 2020 report of the International Agency for Research on Cancer (IARC), cancer is now the most common form of death worldwide ahead of heart disease. The report suggests that many cancers can be prevented, and better diagnoses and treatment could improve outcomes [3]. The World Health Organization (WHO) warns that if current trends con- tinue, the world will see a greater than 100% increase in annual cancer deaths over the next 40 years – from about 9–10 million deaths in 2020 to about 19 million deaths in 2060 [4]. The greatest increase (81%) in new cases will occur in low- and middle-income countries, where survival rates are currently lowest. This is double (40%) the new cancer cases that are expected in high- income countries [4]. The report outlines several steps to save millions of lives worldwide, including (1) controlling tobacco use (currently responsible for 25% of all cancer deaths), (2) vaccinating against hepatitis B to prevent liver cancer, (3) eliminating cervical cancer by vaccinating against HPV, (4) improving screening and treatment, and (5) implementing high-impact can- cer management interventions that bring value for money, and ensure access to palliative care, including pain relief. The report notes that in highincome countries there has been a marked decline (by approximately 20%) in prema- ture deaths due to cancer between the years 2000 and 2015. This is presum- ably due to outstanding research into cancer causes and the development of improved treatments. On the other hand, the report notes that the situation is much less promising in low-income countries where the reduction in cancer mortality during this period was only 5%. Much of this discrepancy is due to inadequate methods for diagnosis and treatment in lowincome countries ver- sus high-income countries [4]. What can be done to improve the diagnoses of cancer and the survival rate, especially in low-income countries? Obviously, early diagnosis and improved diagnostic accuracy are vitally important and I will return to this point later. President Richard Nixon in his January 1971 State of the Union Address to vii viii Foreword the Nation declared war on cancer signing the National Cancer Act into law. This act gave the National Cancer Institute (NCI) unique autonomy within the National Institutes of Health (NIH) with special budgetary authority in the fght against cancer [5]. Many years later, President Barack Obama, hav- ing lost his mother to ovarian cancer, picked up the cause and called for an aggressive war on the disease. In his fnal State of the Union message in 2016 President Obama tasked his vice president—Joe Biden—to spearhead an ini- tiative to cure cancer: “Last year, Vice President Biden said that with a new moonshot, America can cure cancer,” Obama said, noting that Biden had worked with Congress to add resources for the NIH. Obama stated in part “For the loved ones we’ve all lost, for the family, we can still save, let’s make America the country that cures cancer once and for all” [6]. There is no ques- tion of the enormous contributions of the NIH (and many other government- sponsored and private funding agencies in the USA and worldwide) that have helped biomedical researchers understand how cancers arise and how to develop appropriate treatments. The physics of what was required to land a man on the moon was well understood in 1969 (the year of the frst successful moon landing). However, no such unique understanding pertains to cancer. We now know that every type of cancer is different and can arise from a mul- titude of disparate inherited or acquired mutations, and that even within a single type of cancer, individual cancer cells may have varying mutational and phenotypic profles. These considerations pose enormous challenges for the early diagnosis of many cancers and for appropriate interventions to pre- vent cancer metastases. What options are available to minimize the risk of cancer? Obvious life- style changes that can help minimize the risk of cancer include eschewing smoking, maintaining a healthy diet, maintaining a recommended body-mass index, exercising regularly, avoiding excessive sunlight, acquiring appropri- ate vaccinations, and avoiding risky lifestyles [7]. Regular health checkups, including screening for colon, breast, and skin cancers, can help detect can- cers at an early enough stage to improve treatment outcomes, especially among those with increased risk. But what sorts of treatments are available once a patient has been diagnosed with cancer? The American Cancer Society lists seven possible treatment options, namely, surgery, chemotherapy, radia- tion therapy, targeted therapy, immunotherapy, stem cell or bone marrow transplant, and hormone therapy [8]. The NCI provides a similar list of treat- ment options, but also includes a category entitled precision medicine [9]. Targeted therapy and precision medicine are relatively new concepts regard- ing cancer treatment options. Targeted therapy is aimed at the changes in cancer cells that help them grow, divide, and spread [9]. On the other hand, precision medicine helps doctors select treatments that are most likely to help patients based on genetic or other characteristics of their disease [9].