Journal of Cancer 2015, Vol. 6 29 Ivyspring International Publisher Journal of Cancer 2015; 6(1): 29-39. doi: 10.7150/jca.10336 Review Cancer: We Should Not Forget The Past Anna Di Lonardo1 , Sergio Nasi2 , Simonetta Pulciani1 1. National Center for Immunobiologicals Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy. 2. Istituto di Biologia, Medicina molecolare e Nanobiotecnologie (IBMN) CNR, Sapienza University, Rome, Italy. Corresponding author: Simonetta Pulciani, [email protected]. © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/ licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2014.08.14; Accepted: 2014.09.19; Published: 2015.01.01 Abstract Cancer has been in existence longer than human beings, and man has been facing the illness ever since he made his appearance on Earth. Amazingly, the first human cancer gene was cloned only thirty years ago. This, and other extraordinary scientific goals achieved by molecular cancer re- search in the last 30 years, seems to suggest that definitive answers and solutions to this severe disease have been finally found. This was not the case, as cancer still remains to be defeated. To do so, cancer must be first understood. This review highlights how cancer onset and progression has been tackled from ancient times to present day. Old theories and achievements have provided the pillars of cancer understanding, in laying the basis of ‘modern era’ cancer research, are discussed. The review highlights the discovery of oncogenes and suppressor tumor genes, underlining the crucial role of these achievements in cancer diagnosis and therapies. Finally, an overview of how the modern technologies have given impetuous to expedite these goals is also considered. Key words: Cancer theories, oncogenes, genomics. Introduction The scientific path taken to understand cancer is Boveri had no knowledge on the chromosome paved with thousands of theories and scientific find- structure; however, his theory today is considered a ings, from the time of Hippocrates to genomics today. pillar of modern molecular approaches to cancer. The Many of these are fundamental in our modern ap- discovery of the DNA structure and the achievements proaches to the disease. of molecular biology have reaffirmed Boveri’s theory Chemical carcinogenesis was brought to light and given technological support to developments in with the observations of Paracelsus on cancer onset this field. and environmental exposure to chemicals undertaken Without doubt, the first human transforming over six centuries ago (1-3). The relationship between gene, and more broadly, oncogenes and an- cancer and chemicals captured the interest of scien- ti-oncogenes, had been previously theorized by The- tists since the 18th century, and this having had a odor Boveri. greater impact in the last century. This knowledge, Nowadays, even though scientific research previously unproved, is a reality in today’s research moves ahead rapidly, cancer still needs solid and re- and plays a vital role in the understanding of cancer. liable solutions. Nevertheless, science should look Exactly a century ago, in the book, Zur Frage der back to historical achievements in advancing new Entstehung Maligner Tumoren, Boveri presented his theories and data. Considering the past, and review- theory on cancer that was based on chromosomal ing the milestones of every scientific finding could abnormality (4-6). help in molding future experimental approaches in cancer research. http://www.jcancer.org Journal of Cancer 2015, Vol. 6 30 From Pre-History to Boveri (1-3). At this time it was not known how the elements of the environment caused disease; however, this ob- Cancer has been in existence on Earth even be- servation pre-empted the future of chemical carcino- fore the appearance of man, as evidenced by paleon- genesis research, being the first association between tological findings of tumors in animals (1, 2). the work environment and cancer. The first description of human cancer can be A century later, Boerhaave suggested, ‘…that found in the Edwin Smith Papyrus dated 3000 BC that cancer was most likely induced by viruses present in illustrated a case of breast cancer. Other documented water or in soil. Once acquired, the cancer viruses proof includes the Ebers Papyrus dating from 1500 BC remained in the body, and they could be transferred that describes several types of tumors concerning by contagious infections or by heredity’. This theory skin, uterus, stomach, and rectum. These old Egyptian was by no means new, as people during Middle Ages documents recorded cancer as a grave incurable dis- understood that cancer was a contagious disease. ease and associated it to ‘the curse of the gods’ (1). Moreover, at that time the term virus indicated some Interestingly, this belief continued to be accepted right kind of toxic substance, therefore in this respect, up to Hippocrates (460-370 BC), who postulated the Boerhaave’s hypothesis was similar to that of Para- earliest scientific theory about cancer. Hippocrates celsus. However, Boerhaave first introduced the new hypothesized that this disease was correlated to an concept that cancer could be hereditary (1, 2). excess of black bile. He believed that cancers, and In the 18th century the Italian pathologist, G.B. more broadly any disease, developed whenever the Morgagni, founded scientific oncology by performing balance in the four body humours (blood, phlegm, autopsies after death to identify the patient’s disease. yellow bile, and black bile) were lost. Whenever black Consequently, he reported that cancer was the result bile became the dominant humours in some part of of an ‘organ lesion’. the body, this developed cancer. Other scientists and surgeons suggested cancer Hippocrates theory established the foundations was a destructive growth of the organ, caused by their of experimental approaches in understanding and internal structural transformation, or derived from confronting cancer, thereafter practiced by all scien- coagulated lymph (1, 2). tists. Claudius Galen (130-200), a Greek physician During the 18th century, different physicians who practiced medicine in Rome, implemented the expanded the hypothesis about the association be- Hippocrates theory. He proposed that black bile tween cancers and chemical exposure. Their observa- caused incurable cancer, whereas yellow bile caused tions had recalled the Paracelsus hypothesis, and this curable cancer. established the new and modern approach of cancer Additionally, the terms and words used to name epidemiology. John Hill associated the use of snuff this disease, and whatever it was associated with, with nasal polyps. Bernardino Ramazzini associated were created by these early ‘scientists’. Hippocrates breast cancer with reproductive factors (1, 2). Inter- used the word carcinoma, comparing the disease to a estingly, in 1775 Percivall Pott noticed that chimney crab (Καρκίνος) that adheres to its surroundings with sweepers frequently developed cancer of the scrotum his claws (1, 2). The physician Celsus (25 BC-50 ), later in later life, and suggested that soot was the cause of translated this word into cancer, the Latin word for this type of cancer. In the last decades of the 19th cen- crab. Galen (130-200) described tumors using the tury, Ludwig Rehn, observed an association between Greek term for swelling, oncos. exposure to the aniline dye and bladder cancer in in- In the Middle Ages, religious beliefs inhibited dustrial workers (2, 3). the advancement of knowledge, and people began to The use of the microscope represented an op- believe that cancer was an infectious disease. portunity for researchers to investigate tumors in Eventually, medical science gained a foothold great detail. Rudolf Virchow stated that ‘cancer is a during the Renaissance when scientists began per- disease of cells’, and David Hansemann proposed, forming autopsies, combining the study of the human ‘The cell of the malignant tumor is a cell with a certain body and that of cancer, leading to important abnormal chromatin content’ (2, 4, 6). achievements. In the 16th century, the anatomist An- At the beginning of the 20th century, several re- dreas Vesalius and others were able to demonstrate searchers experimentally confirmed that specific the non-existence of black bile. Nevertheless, Hip- chemicals in the workplace and environment were pocrates’ theory still continued to have great number correlated with the carcinogenic process, demon- of supporters, and it took some time before it was strating their multistage and multifactor nature. superseded by a new hypotheses. In the same century, Katsusaburo Yamagiwa and Koichi Ichikawa, in 1915, Paracelsus studied tumors of mine workers, and were able to induce cancer in rabbits by applying coal suggested there were deposits of sulfur and arsenic tar to the skin of these laboratory animals (3). Addi- salts in blood of these workers, causing their cancers http://www.jcancer.org Journal of Cancer 2015, Vol. 6 31 tionally, at this time Theodor Boveri had expanded From Boveri to Oncogenes and Anti- the Hansemann theory. It is worthwhile to mention Oncogenes what Boveri wrote, ‘tumor growth is based on ..…a particular, incorrect chromosome combination which Ellerman and Bang in 1908, induced