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Cancers
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Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient...
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Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2010) | Viewed by 93587

Special Issue Editor

Prof. Dr. Michael W. Retsky

E-Mail Website
Guest Editor
Department of Targeted Intervention, University College London, Gower Street, London WC1E 6BT, UK
Interests: cancer research; electron beam technology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bimodal relapse patterns in early stage breast cancer are observed in multiple databases. This is unexplainable with the long-accepted continuous growth model. In order to explain these data, it was proposed with the aid of computer simulations that micrometastatic tumor growth includes periods of temporary dormancy and furthermore, surgery to remove primary tumors kick-starts growth of dormant distant disease. Apparently over half of all relapses are accelerated by such means. Two previously unreported modes of relapse were proposed as the dominant paths leading to treatment failure in early stage breast cancer. Single dormant cells are induced into division by surgery, an effect that increases with primary size. Also angiogenesis is induced in dormant avascular micrometastases mainly for premenopausal patients with positive lymph nodes. This theory may provide new explanations for a wide variety of clinical breast cancer features that were previously thought to be unconnected. In addition to the relapse patterns, this is proposed to at least partly explain paradoxical mammography data for women age 40-49, that the benefit of adjuvant chemotherapy is most effective by far for premenopausal node positive patients, breast cancer in young women is often labeled “aggressive”, the overall heterogeneous nature of breast cancer, and the racial disparity in outcome. To present a forum for focused discussion, this special issue of Cancers will be devoted to papers that argue for and against this new theory.

Dr. Michael W. Retsky
Guest Editor

Keywords

  • breast cancer
  • dormancy
  • angiogenesis
  • distant relapse
  • mammography
  • adjuvant chemotherapy
  • racial disparities in outcome
  • heterogeneity
  • aggressiveness
  • bimodal relapse pattern
  • surgery

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Published Papers (9 papers)

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Research

Jump to: Review

285 KiB  
Article
Does Secondary Inflammatory Breast Cancer Represent Post-Surgical Metastatic Disease?
by Salman Hashmi, Ladan Zolfaghari and Paul H. Levine
Cancers 2012, 4(1), 156-164; https://doi.org/10.3390/cancers4010156 - 20 Feb 2012
Cited by 7 | Viewed by 7231
Abstract
The phenomenon of accelerated tumor growth following surgery has been observed repeatedly and merits further study. Inflammatory breast carcinoma (IBC) is widely recognized as an extremely aggressive malignancy characterized by micrometastasis at the time of diagnosis, with one interesting subgroup defined as secondary [...] Read more.
The phenomenon of accelerated tumor growth following surgery has been observed repeatedly and merits further study. Inflammatory breast carcinoma (IBC) is widely recognized as an extremely aggressive malignancy characterized by micrometastasis at the time of diagnosis, with one interesting subgroup defined as secondary IBC where pathologically identifiable IBC appears after surgical treatment of a primary non-inflammatory breast cancer. One possible mechanism can be related to the stimulation of dormant micrometastasis through local angiogenesis occurring as part of posttraumatic healing. In this report, we review cases of secondary IBC and others where localized trauma was followed by the appearance of IBC at the traumatized site that have been identified by our IBC Registry (IBCR) and hypothesize that angiogenesis appearing as part of the healing process could act as an accelerant to an otherwise latent breast malignancy. It is therefore possible that secondary IBC can be used as a model to support local angiogenesis as an important contributor to the development of an aggressive cancer. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
317 KiB  
Article
Tumor Cell Seeding During Surgery—Possible Contribution to Metastasis Formations
by Pachmann Katharina
Cancers 2011, 3(2), 2540-2553; https://doi.org/10.3390/cancers3022540 - 8 Jun 2011
Cited by 15 | Viewed by 8310
Abstract
In spite of optimal local control in breast cancer, distant metastases can develop as a systemic part of this disease. Surgery is suspected to contribute to metastasis formation activating dormant tumor cells. Here we add data that seeding of cells during surgery may [...] Read more.
In spite of optimal local control in breast cancer, distant metastases can develop as a systemic part of this disease. Surgery is suspected to contribute to metastasis formation activating dormant tumor cells. Here we add data that seeding of cells during surgery may add to the risk of metastasis formation. The change in circulating epithelial tumor cells (CETC) was monitored in 66 breast cancer patients operated on with breast conserving surgery or mastectomy and during the further course of the disease, analyzing CETC from unseparated white blood cells stained with FITC-anti-EpCAM. An increase in cell numbers lasting until the start of chemotherapy was observed in about one third of patients. It was more preeminent in patients with low numbers of CETC before surgery and, surprisingly, in patients without involved lymph nodes. Patients with the previously reported behavior—Reincrease in cell numbers during adjuvant chemotherapy and subsequent further increase during maintenance therapy—were at increased risk of relapse. In addition to tumor cells already released during growth of the tumor, cell seeding during surgery may contribute to the early peak of relapses observed after removal of the primary tumor and chemotherapy may only marginally postpone relapse in patients with aggressively growing tumors. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
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Review

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128 KiB  
Review
Extracellular NM23 Signaling in Breast Cancer: Incommodus Verum
by Iain L.O. Buxton and Nucharee Yokdang
Cancers 2011, 3(3), 2844-2857; https://doi.org/10.3390/cancers3032844 - 6 Jul 2011
Cited by 11 | Viewed by 6735
Abstract
The notion that breast cancers can survive in an individual patient in a dormant state only to grow as metastatic disease in the future, is in our view incontrovertibly established. Convincing too is the evidence that surgery to remove the primary tumor often [...] Read more.
The notion that breast cancers can survive in an individual patient in a dormant state only to grow as metastatic disease in the future, is in our view incontrovertibly established. Convincing too is the evidence that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. Accepting that many deaths due to breast cancer might be averted were we to understand the cellular mechanisms underlying escape from dormancy, we have examined the extracellular signals produced by breast cancers derived from women with metastatic breast disease. In this perspective, we explore the role of extracellular nucleotide signaling that we have proposed constitutes a pathological axis from the transformed tumor cell to the endothelium in the service of intravasation, dissemination, extravasation and angiogenesis. A role for the dinucleotide kinase NM23/NDPK (nucleoside diphosphate kinase) secreted by breast tumor cells in the generation of signals that stimulate vascular leakiness, anti-thrombosis, endothelial migration and growth, constitutes a mechanistic basis for escape from latency and offers putative therapeutic targets for breast cancer management not previously appreciated. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
776 KiB  
Review
An Evolutionary Explanation for the Perturbation of the Dynamics of Metastatic Tumors Induced by Surgery and Acute Inflammation
by Alberto Carmona Bayonas
Cancers 2011, 3(1), 945-970; https://doi.org/10.3390/cancers3010945 - 2 Mar 2011
Cited by 1 | Viewed by 9454
Abstract
Surgery has contributed to unveil a tumor behavior that is difficult to reconcile with the models of tumorigenesis based on gradualism. The postsurgical patterns of progression include unexpected features such as distant interactions and variable rhythms. The underlying evidence can be summarized as [...] Read more.
Surgery has contributed to unveil a tumor behavior that is difficult to reconcile with the models of tumorigenesis based on gradualism. The postsurgical patterns of progression include unexpected features such as distant interactions and variable rhythms. The underlying evidence can be summarized as follows: (1) the resection of the primary tumor is able to accelerate the evolution of micrometastasis in early stages, and (2) the outcome is transiently opposed in advanced tumors. The objective of this paper is to give some insight into tumorigenesis and surgery-related effects, by applying the concepts of the evolutionary theory in those tumor behaviors that gompertzian and tissular-centered models are unable to explain. According to this view, tumors are the consequence of natural selection operating at the somatic level, which is the basic mechanism of tumorigenesis, notwithstanding the complementary role of the intrinsic constrictions of complex networks. A tumor is a complicated phenomenon that entails growth, evolution and development simultaneously. So, an evo-devo perspective can explain how and why tumor subclones are able to translate competition from a metabolic level into neoangiogenesis and the immune response. The paper proposes that distant interactions are an extension of the ecological events at the local level. This notion explains the evolutionary basis for tumor dormancy, and warns against the teleological view of tumorigenesis as a process directed towards the maximization of a concrete trait such as aggressiveness. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
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185 KiB  
Review
Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?
by William W. Tseng, Niloofar Fadaki and Stanley P. Leong
Cancers 2011, 3(1), 730-746; https://doi.org/10.3390/cancers3010730 - 21 Feb 2011
Cited by 11 | Viewed by 8980
Abstract
According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable [...] Read more.
According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
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249 KiB  
Review
Why Victory in the War on Cancer Remains Elusive: Biomedical Hypotheses and Mathematical Models
by Leonid Hanin
Cancers 2011, 3(1), 340-367; https://doi.org/10.3390/cancers3010340 - 17 Jan 2011
Cited by 14 | Viewed by 8828
Abstract
We discuss philosophical, methodological, and biomedical grounds for the traditional paradigm of cancer and some of its critical flaws. We also review some potentially fruitful approaches to understanding cancer and its treatment. This includes the new paradigm of cancer that was developed over [...] Read more.
We discuss philosophical, methodological, and biomedical grounds for the traditional paradigm of cancer and some of its critical flaws. We also review some potentially fruitful approaches to understanding cancer and its treatment. This includes the new paradigm of cancer that was developed over the last 15 years by Michael Retsky, Michael Baum, Romano Demicheli, Isaac Gukas, William Hrushesky and their colleagues on the basis of earlier pioneering work of Bernard Fisher and Judah Folkman. Next, we highlight the unique and pivotal role of mathematical modeling in testing biomedical hypotheses about the natural history of cancer and the effects of its treatment, elaborate on model selection criteria, and mention some methodological pitfalls. Finally, we describe a specific mathematical model of cancer progression that supports all the main postulates of the new paradigm of cancer when applied to the natural history of a particular breast cancer patient and fit to the observables. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
141 KiB  
Review
Rational and Irrational Issues in Breast Cancer Screening
by Cornelia J. Baines
Cancers 2011, 3(1), 252-266; https://doi.org/10.3390/cancers3010252 - 11 Jan 2011
Cited by 10 | Viewed by 13082
Abstract
Evidence on the efficacy of breast screening from randomized controlled trials conducted in the last decades of the 1900s is reviewed. For decades, controversy about their results has centered on the magnitude of benefit in terms of breast cancer mortality reduction that can [...] Read more.
Evidence on the efficacy of breast screening from randomized controlled trials conducted in the last decades of the 1900s is reviewed. For decades, controversy about their results has centered on the magnitude of benefit in terms of breast cancer mortality reduction that can be achieved. However more recently, several expert bodies have estimated the benefits to be smaller than initially expected and concerns have been raised about screening consequences such as over-diagnosis and unnecessary treatment. Trials with substantial mortality reduction have been lauded and others with null effects have been critiqued. Critiques of the Canadian National Breast Screening Study are refuted. Extreme responses by screening advocates to the United States Preventive Services Task Force 2009 guidelines are described. The role vested interests play in determining health policy is clearly revealed in the response to the guidelines and should be more generally known. A general reluctance to explore unexpected results or to accept new paradigms is briefly discussed. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
182 KiB  
Review
Surgery as a Double-Edged Sword: A Clinically Feasible Approach to Overcome the Metastasis-Promoting Effects of Surgery by Blunting Stress and Prostaglandin Responses
by Marganit Benish and Shamgar Ben-Eliyahu
Cancers 2010, 2(4), 1929-1951; https://doi.org/10.3390/cancers2041929 - 24 Nov 2010
Cited by 32 | Viewed by 10624
Abstract
Surgery remains an essential therapeutic approach for most solid malignancies, including breast cancer. However, surgery also constitutes a risk factor for promotion of pre-existing micrometastases and the initiation of new metastases through several mechanisms, including the release of prostaglandins and stress hormones (e.g., [...] Read more.
Surgery remains an essential therapeutic approach for most solid malignancies, including breast cancer. However, surgery also constitutes a risk factor for promotion of pre-existing micrometastases and the initiation of new metastases through several mechanisms, including the release of prostaglandins and stress hormones (e.g., catecholamines and glucocorticoids). However, the perioperative period also presents an opportunity for cell mediated immunity (CMI) and other mechanisms to eradicate or control minimal residual disease, provided that the deleterious effects of surgery are minimized. Here, we discuss the key role of endogenous stress hormones and prostaglandins in promoting the metastatic process through their direct impact on malignant cells, and through their deleterious impact on anti-cancer CMI. We further discuss the effects of anesthetic techniques, the extent of surgery, pain alleviation, and timing within the menstrual cycle with respect to their impact on tumor recurrence and physiological stress responses. Last, we suggest an attractive perioperative drug regimen, based on a combination of a cyclooxygenase (COX)-2 inhibitor and a β-adrenergic blocker, which we found effective in attenuating immune suppression and the metastasis-promoting effects of surgery in several tumor models. This regimen is clinically applicable, and could potentially promote disease free survival in patients operated for breast and other types of cancer. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
343 KiB  
Review
Surgery Triggers Outgrowth of Latent Distant Disease in Breast Cancer: An Inconvenient Truth?
by Michael Retsky, Romano Demicheli, William Hrushesky, Michael Baum and Isaac Gukas
Cancers 2010, 2(2), 305-337; https://doi.org/10.3390/cancers2020305 - 30 Mar 2010
Cited by 63 | Viewed by 19395
Abstract
We review our work over the past 14 years that began when we were first confronted with bimodal relapse patterns in two breast cancer databases from different countries. These data were unexplainable with the accepted continuous tumor growth paradigm. To explain these data, [...] Read more.
We review our work over the past 14 years that began when we were first confronted with bimodal relapse patterns in two breast cancer databases from different countries. These data were unexplainable with the accepted continuous tumor growth paradigm. To explain these data, we proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. We also suggested that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. These iatrogenic events are apparently very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from a variety of historical, clinical, and scientific perspectives and consider how dormancy and surgery-driven escape from dormancy would be observed and what this would mean. Dormancy can be identified in these diverse data but most conspicuous is the sudden synchronized escape from dormancy following primary surgery. On the basis of our findings, we suggest a new paradigm for early stage breast cancer. We also suggest a new treatment that is meant to stabilize and preserve dormancy rather than attempt to kill all cancer cells as is the present strategy. Full article
(This article belongs to the Special Issue Surgery Induced Tumorigenesis in Breast and Other Cancers: An Inconvenient Truth?)
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