An alternative model of cancer cell growth and metastasis (original) (raw)
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Proposal for a new model of breast cancer metastatic development
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 1997
The commonly accepted theory of breast cancer metastatic development assumes continuous tumor growth from tumor seeding until documentation of clinical recurrence. In particular, Gompertzian growth kinetics is currently the theoretical cornerstone of the natural history of breast cancer, and has been widely utilized for planning treatments. To verify agreement between findings and the implications of the continuous growth model, several published papers about the natural history of breast cancer after removal of the primary tumor were reviewed. Also, findings from animal models concerning metastasis biology were considered. The continuous growth model failed in important ways upon this critical reappraisal. As an alternative, the tumor dormancy hypothesis was considered to provide a more reasonable description of tumor recurrence. Moreover, primary tumor removal was revealed as a potentially perturbing factor for metastasis development. A new general outline of metastatic developmen...
On the Origin of Cancer Metastasis
Critical Reviews in Oncogenesis, 2013
Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis. These involve an epithelial mesenchymal transition, an accumulation of mutations in stem cells, a macrophage facilitation process, and a macrophage origin involving either transformation or fusion hybridization with neoplastic cells. Many of the properties of metastatic cancer cells are also seen in normal macrophages. A macrophage origin of metastasis can also explain the long-standing "seed and soil" hypothesis and the absence of metastasis in plant cancers. The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management.
European Journal of Cancer, 2005
This historical perspective on breast cancer tells us how and why certain therapeutic eras have reached ascendancy and then declined. Therapeutic revolutions occur after a crisis develops when there is a general recognition that clinical interventions are not producing positive results predicted by the prevailing paradigm. The attitude of pre-modern surgeons was influenced by the very real possibility of doing more harm than good by operating upon women with breast cancer. Up until Halsted, the general consensus was clearly that, unless forced by the circumstances, surgical resection should be avoided for disease much more advanced than very early stage tumours (the cacoethesis of Celsus). Twentieth century progress in antisepsis, anaesthesia, and surgery changed this point of view. The first three quarters of that century saw more and more aggressive operations performed while the last quarter century reversed this trend, with reduction of the size of breast cancer operations based largely on the teachings of Fisher. A new crisis is upon us now in that trials of early detection have resulted in unexpected disadvantages to certain subgroups and there is previously unreported structure in early hazard of relapse, clinical data that suggests the act of surgery might accelerate the appearance of distant metastases. The explanation we propose that agrees with these results, as well as physicians of antiquity, is that surgery can induce angiogenesis and proliferation of distant dormant micrometastases, especially in young patients with positive nodes.
Carcinoma Metastasis – An Approach to Models
Journal of Carcinogenesis & Mutagenesis, 2011
Background: Epithelium is separated from other tissues in the body by the basal membrane. When respecting this boundary, atypical epithelial growth does not cause serious illness in most cases. Therefore, carcinoma in situ is considered to be a non-malignant condition. However, the situation is quite different if the epithelial cells do not respect the natural boundaries in the tissue, a condition that is often referred to as cancer. Uncontrolled invasive growth is indeed the main characteristic of malignancy, and metastasis is in most cases the reason why cancer patients die. Materials and methods: The purpose of this article is to highlight how carcinoma cells, nature, can be classified in three steps, in respect to the first local infiltration of malignant epithelium. The literature referred to is selected on the basis that the views advocated are not controversial, and not represent individual findings. Moreover, some considerations are based on the authors own experience in clinical and molecular basic research. Results: The main characteristics of invasive cellular behavior are modified adhesion and a transition from fixed cells to a migratory phenotype. Invasion is made possible by the degradation of extracellular components. We only know fragments of the gene and phenotypic changes that enable cancers origin of behavior, but there is evidence that chemokines play a central role in the directional spread of motile cells. However, the most common characteristic of carcinoma cells is their loss of cell polarity. Interpretation: The complexity of multicellular organisms is staggering. Artificial and highly simplified model systems are therefore cancer researcher's most important tools. To be significant, such results must be translated and verified to the in vivo situation. In addition, generality in cancer research finding must be given greater importance, since individual results, not can form the basis for new treatment regimes. Today's biggest challenge for researchers is therefore to be able to collate the enormous diversity of molecular biological knowledge that daily runs.
Cancer, 2003
BACKGROUND. There has been great debate regarding the importance of ductal carcinoma in situ (DCIS) in the breast. Autopsy results that demonstrate a much greater number of these lesions compared with the number of invasive carcinomas, and the numbers of deaths from breast carcinoma each year have been cited as evidence that DCIS rarely leads to invasion and death. These analyses have overlooked the fact that, to sustain a rate of detection each year, there would have to be a reservoir of undetected breast carcinomas growing in the population. The authors developed a simple model that makes this clear. In addition, complex phenomena have been suggested to explain why invasive breast disease may grow more rapidly among very young women and more slowly among the very old. A simple model provides some insight that may simplify the explanation of these observations.
Cancer Metastases: So Close and So Far
Journal of the National Cancer Institute, 2015
Metastases are tumors that develop at a distance from their primary origin and are responsible for the death of 90% of cancer patients. For over a century the notion of seed (migrating cells) and soil (the locus where those cells anchor) provided an accurate account of which were the protagonists in their genesis. Despite aggressive efforts to unravel the dynamics involving migrating cells and the niche in which they anchor, explanations of this process remain ill-defined and controversial. The controversy is generated by the different premises that researchers adopt to integrate the vast amount of data collected at different levels of biological organization. The so-far hegemonic theory of cancer and its metastases has been the somatic mutation theory (SMT) and a number of its variants: They consider that cancers and their metastases represent a cell-based, genetic and molecular disease. This interpretation has been challenged by the tissue organization field theory (TOFT), which considers instead that cancer is a tissue-based disease, akin to development gone awry. In this Commentary, the merits of both theories are compared now in the context of metastases. Based on the epistemological shortcomings of the SMT and the acknowledged failure of therapeutic approaches based on this theory, we conclude that TOFT explains comprehensibly carcinogenesis and the appearance of metastases. Metastases are defined as secondary tumors that develop at a distance from their primary originators; they are the cause of death for 90% of cancer patients (1). Much has been written and done in the field of cancer metastases since Stephen Paget's seminal work in the 19 th century that established the notion of seed and soil (2). Notwithstanding, despite concerted theoretical, clinical, and experimental efforts, the prevailing consensus is that metastases are not explained accurately, and, more importantly, they are far from being successfully managed (3-5). This widely acknowledged failure is not for lack of trying. Both epidemiologic and experimental evidence confirm the consensus that metastases remain an obscure subject. Buttressing this assessment, I. J. Fidler, an acknowledged pioneer in the field, recently surmised the feelings of most expert contributors to a multi-author issue of Seminars in Cancer Biology when he candidly declared that "The field is open!" (6). Encouraged by Fidler's implicit invitation to contribute to the resolution of the cancer metastases puzzle and by our own bench experience, we will be comparing views on this subject, first from the perspective of the somatic mutation theory (SMT) plus its variants (7-11) and next from the tissue organization field theory of carcinogenesis (TOFT) (12-14). In order to propose changes in perspective, we will begin by outlining which are the premises adopted by these two main distinctive theories. Under What Premises Have Explanations of Metastases Been Interpreted?
Evolutionary Basis of Cancer Metastasis and Its Implication to a Lasting Cure
This review is intended to take us through a journey on how cancer had been treated and highlight the paradigm shift in understanding its treatment since adoption of evolution concept and hope to point to a possible future breakthrough in cancer management. Researchers estimate there will be 26 million or more new cases a year by 2030, and some 17 million cancer deaths yearly. The US president in 1971 Richard Nixon proposed the war on cancer in a bid to find lasting cure to cancer in the space of 25 years. An evaluation was carried out after 25 years, which, showed that although there had been major breakthrough in the battle against cancer yet the war continues and we are not yet close to a definite victory with local invasion, and distant metastasis that is resistant to conventional therapy being the major causes of death. This attitude of cancer cells had been more understood in the light of ecology and evolution in recent years as the Darwinian theory of evolution by natural selection now becomes a theoretical framework for the study of cancer behaviour. However, the implication of this eye opener to the cure of cancer had to be more highlighted if the moon shot war against cancer as declared by President Obama in 2016 would be successful. Early diagnosis taking into cognizance polyploidy parameters, more specific choice and scheduling of cancer treatment; selective toxicity, Inhibiting other chemicals or factors that initiate and sustains angiogenesis in cancer cells (tumour or human specific), supporting the immune system, boosting normal cell fitness and Restoring a more normal ecological niche may be the answer we have long sorted for as we strive to find a lasting cure to cancer.
Proceedings of The National Academy of Sciences, 2003
According to the present view, metastasis marks the end in a sequence of genomic changes underlying the progression of an epithelial cell to a lethal cancer. Here, we aimed to find out at what stage of tumor development transformed cells leave the primary tumor and whether a defined genotype corresponds to metastatic disease. To this end, we isolated single disseminated cancer cells from bone marrow of breast cancer patients and performed singlecell comparative genomic hybridization. We analyzed disseminated tumor cells from patients after curative resection of the primary tumor (stage M0), as presumptive progenitors of manifest metastasis, and from patients with manifest metastasis (stage M1). Their genomic data were compared with those from microdissected areas of matched primary tumors. Disseminated cells from M0-stage patients displayed significantly fewer chromosomal aberrations than primary tumors or cells from M1-stage patients (P < 0.008 and P < 0.0001, respectively), and their aberrations appeared to be randomly generated. In contrast, primary tumors and M1 cells harbored different and characteristic chromosomal imbalances. Moreover, applying machine-learning methods for the classification of the genotypes, we could correctly identify the presence or absence of metastatic disease in a patient on the basis of a single-cell genome. We suggest that in breast cancer, tumor cells may disseminate in a far less progressed genomic state than previously thought, and that they acquire genomic aberrations typical of metastatic cells thereafter. Thus, our data challenge the widely held view that the precursors of metastasis are derived from the most advanced clone within the primary tumor.