The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory.
TL;DR: Based on epistemological and experimental evidence, it is argued that the TOFT compellingly explains carcinogenesis, while placing it within an evolutionarily relevant context.
Abstract: The somatic mutation theory (SMT) of cancer has been and remains the prevalent theory attempting to explain how neoplasms arise and progress. This theory proposes that cancer is a clonal, cell-based disease, and implicitly assumes that quiescence is the default state of cells in multicellular organisms. The SMT has not been rigorously tested, and several lines of evidence raise questions that are not addressed by this theory. Herein, we propose experimental strategies that may validate the SMT. We also call attention to an alternative theory of carcinogenesis, the tissue organization field theory (TOFT), which posits that cancer is a tissue-based disease and that proliferation is the default state of all cells. Based on epistemological and experimental evidence, we argue that the TOFT compellingly explains carcinogenesis, while placing it within an evolutionarily relevant context.
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Journal Article•
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore
PL02-05
All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.
2,737 citations
25 May 2011
TL;DR: A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell.
Abstract: Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.
2,019 citations
TL;DR: Most educated people nowadays know that the authors share over 98% of their DNA with chimpanzees, but many humans may experience a frisson on learning this fact, which gives some sense of the existential horror that Darwin's contemporaries had to deal with.
Abstract: Most educated people nowadays know that we share over 98% of our DNA with chimpanzees. It does not disconcert us. The Victorians may have reacted with outrage to the proposition that we share our ancestors with the great apes, but we now live comfortably with the knowledge of our cousinhood.
We also share 50% of our DNA with bananas. This is a little harder to come to terms with. We cannot know how the bananas feel about it, but many humans may experience a frisson on learning this fact. The frisson may only be a faint echo of the existential horror that Darwin's contemporaries had to deal with. All the same, it gives us some sense of the blow that he delivered to their self‐esteem.
Modern doctors have a somewhat peculiar relationship with Darwinism and evolutionary biology. The problem is not one of disbelief. Only a small minority of doctors still have anti‐Darwinian views about the origin of species or the descent of man. No doubt they continue to defend these in the same way that the Inquisition …
417 citations
TL;DR: The TGF-β signalling pathway, its involvement in cancer and current therapeutic approaches, and several molecular targets with great potential in therapeutic interventions have been identified are discussed.
Abstract: The transforming growth factor-β (TGF-β) system signals via protein kinase receptors and SMAD mediators to regulate a large number of biological processes. Alterations of the TGF-β signalling pathway are implicated in human cancer. Prior to tumour initiation and early during progression, TGF-β acts as a tumour suppressor; however, at later stages, it is often a tumour promoter. Knowledge about the mechanisms involved in TGF-β signal transduction has allowed a better understanding of cancer progression, invasion, metastasis and epithelial-to-mesenchymal transition. Furthermore, several molecular targets with great potential in therapeutic interventions have been identified. This review discusses the TGF-β signalling pathway, its involvement in cancer and current therapeutic approaches.
353 citations
TL;DR: Recent data and molecular mechanisms relevant to morphogenetic fields: large-scale systems of physical properties that have been proposed to store patterning information during embryogenesis, regenerative repair, and cancer suppression that ultimately controls anatomy are reviewed.
Abstract: Establishment of shape during embryonic development, and the maintenance of shape against injury or tumorigenesis, requires constant coordination of cell behaviors toward the patterning needs of the host organism. Molecular cell biology and genetics have made great strides in understanding the mechanisms that regulate cell function. However, generalized rational control of shape is still largely beyond our current capabilities. Significant instructive signals function at long range to provide positional information and other cues to regulate organism-wide systems properties like anatomical polarity and size control. Is complex morphogenesis best understood as the emergent property of local cell interactions, or as the outcome of a computational process that is guided by a physically encoded map or template of the final goal state? Here I review recent data and molecular mechanisms relevant to morphogenetic fields: large-scale systems of physical properties that have been proposed to store patterning information during embryogenesis, regenerative repair, and cancer suppression that ultimately controls anatomy. Placing special emphasis on the role of endogenous bioelectric signals as an important component of the morphogenetic field, I speculate on novel approaches for the computational modeling and control of these fields with applications to synthetic biology, regenerative medicine, and evolutionary developmental biology.
201 citations
References
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Book•
01 Jan 1962
TL;DR: The Structure of Scientific Revolutions as discussed by the authors is a seminal work in the history of science and philosophy of science, and it has been widely cited as a major source of inspiration for the present generation of scientists.
Abstract: A good book may have the power to change the way we see the world, but a great book actually becomes part of our daily consciousness, pervading our thinking to the point that we take it for granted, and we forget how provocative and challenging its ideas once were-and still are. "The Structure of Scientific Revolutions" is that kind of book. When it was first published in 1962, it was a landmark event in the history and philosophy of science. And fifty years later, it still has many lessons to teach. With "The Structure of Scientific Revolutions", Kuhn challenged long-standing linear notions of scientific progress, arguing that transformative ideas don't arise from the day-to-day, gradual process of experimentation and data accumulation, but that revolutions in science, those breakthrough moments that disrupt accepted thinking and offer unanticipated ideas, occur outside of "normal science," as he called it. Though Kuhn was writing when physics ruled the sciences, his ideas on how scientific revolutions bring order to the anomalies that amass over time in research experiments are still instructive in our biotech age. This new edition of Kuhn's essential work in the history of science includes an insightful introductory essay by Ian Hacking that clarifies terms popularized by Kuhn, including paradigm and incommensurability, and applies Kuhn's ideas to the science of today. Usefully keyed to the separate sections of the book, Hacking's essay provides important background information as well as a contemporary context. Newly designed, with an expanded index, this edition will be eagerly welcomed by the next generation of readers seeking to understand the history of our perspectives on science.
36,808 citations
"The tissue organization field theor..." refers background in this paper
...The Structure of Scientific Revolutions....
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...In 1962, Kuhn gave the word ‘‘paradigm’’ its contemporary meaning in the Preface of his influential book, The Structure of Scientific Revolutions [69], and defined it as ‘‘a universally recognized scientific achievement(s) that for a time provide model problems and solutions to a community of practitioners.’’...
[...]
...In 1962, Kuhn gave the word ‘‘paradigm’’ its contemporary meaning in the Preface of his influential book, The Structure of Scientific Revolutions [69], and defined it as ‘‘a universally recognized scientific achievement(s) that for a time provide model problems and solutions to a community of practitioners....
[...]
34,393 citations
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
TL;DR: The determination in 1953 of the structure of deoxyribonucleic acid (DNA), with its two entwined helices and paired organic bases, was a tour de force in X-ray crystallography and opened the way for a deeper understanding of perhaps the most important biological process.
Abstract: The determination in 1953 of the structure of deoxyribonucleic acid (DNA), with its two entwined helices and paired organic bases, was a tour de force in X-ray crystallography. But more significantly, it also opened the way for a deeper understanding of perhaps the most important biological process. In the words of Watson and Crick: "It has not escaped our notice that the specific pairing that we have postulated immediately suggests a possible copying mechanism for the genetic material." [Obituary of Francis Crick:
9,946 citations
01 Jan 1976
TL;DR: For centuries knowledge meant proven knowledge, proven either by the power of the intellect or by the evidence of the senses as discussed by the authors. But the notion of proven knowledge was questioned by the sceptics more than two thousand years ago; but they were browbeaten into confusion by the glory of Newtonian physics.
Abstract: For centuries knowledge meant proven knowledge — proven either by the power of the intellect or by the evidence of the senses. Wisdom and intellectual integrity demanded that one must desist from unproven utterances and minimize, even in thought, the gap between speculation and established knowledge. The proving power of the intellect or the senses was questioned by the sceptics more than two thousand years ago; but they were browbeaten into confusion by the glory of Newtonian physics. Einstein’s results again turned the tables and now very few philosophers or scientists still think that scientific knowledge is, or can be, proven knowledge. But few realize that with this the whole classical structure of intellectual values falls in ruins and has to be replaced: one cannot simply water down the ideal of proven truth - as some logical empiricists do — to the ideal of’probable truth’1 or — as some sociologists of knowledge do — to ‘truth by [changing] consensus’.2
4,969 citations
Additional excerpts
...strengthens the framework of the theory [66]....
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