Breast cancer is a heterogeneous group of neoplasms originating from the epithelial cells lining the milk ducts. Today, clinical evaluation of tumor heterogeneity is an emergent issue to improve clinical oncology. But according to our presumptions, the lack of gombertzian growth from the beginning is also a consequence of tumor heterogeneity. Evaluating tumor heterogeneity in immunohistochemistrystained breast cancer tissue steven j potts1, joseph s krueger1, nicholas d landis1, david a eberhard2, g. Familial and hereditary tumors recent results in cancer. Somatic variations in 46 pairs of matched primaryliver metastatic tumors and 42 primary tumors. Epigenetic heterogeneity in cancer biomarker research. The issue of tumor heterogeneity is real, and it is present on several different levels. Moore1,2,4 1institute for quantitative biomedical sciences, the geisel school of medicine, dartmouth college, one. How does it affect the natural history of human cancersand their unnatural history in the face of cancer therapeutics. However, the most complex issue is intratumor heterogeneity ith as a spatial and temporal phenomenon more or less distinct in every single patient.
Tumor heterogeneity refers to the difference between genotype and phenotype of tumor cells in different parts of the same malignancy or in different parts of the same patient. By comparing multiple subpopulations from different anatomic locations, we have inferred pathways of cancer progression and the organization of tumor growth. Sep 19, 20 if genetic heterogeneity within tumors is low, then the differentiation of cancer stem cells into nontumorigenic progeny could be the major driver of heterogeneity figure 4. Analyses from bcacs large resource of genetic and environmental risk factors, tissue microarrays and clinical data, have revealed important tumor markers that delineate the etiologic heterogeneity of breast cancer. In the case of permitted digital reproduction, please credit the national cancer institute as the source and link to the original nci product using the original products title.
Intratumor heterogeneity illuminates a tumors life history. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. Heterogeneity of tumor sizes in multiple pulmonary. Clinicians and pathologists are well acquainted with marked variability in clinical. However, developments in highthroughput singlecell rna sequencing scrnaseq may now provide the statistical power to dissect the diverse cellular populations of tumors. Breast cancer tumor characterization studies national.
Many studies of heterogeneity have had prespecified markers for tumor. Together, they impact patient treatment and outcomes. Heterogeneity is evident between cancers from different patients inter tumor heterogeneity and within a single tumor intra tumor heterogeneity. Deciphering intratumor heterogeneity and temporal acquisition of. Jun 04, 2016 although initial responses to cancer therapy might be effective, eventual relapse is still possible, and often these new tumours are resistant to the previous therapy. Although the concept of patient heterogeneity is well known to any practicing clinician, a more detailed understanding of the biologic changes that underscore the clinical picture is beginning to emerge. Nci dictionary of cancer terms national cancer institute. The first three panels depict different aspects of cancer genome evolution, which all need to be understood to develop improved evolutionary therapeutics panel four. Sep 29, 2016 tumor heterogeneity has been suggested based on clinical and pathological findings.
Modes, mechanisms, ecosystems, and evolutionary therapeutics. John grisham says the tumor is the most important book he has ever written. Intratumor genetic heterogeneity and mortality in head and neck cancer. Radical the science, culture and history of breast cancer in america by kate pickert. In polygenomic tumors, we show that heterogeneity can be ascribed to a few clonal subpopulations, rather than a series of gradual intermediates. If genetic heterogeneity within tumors is low, then the differentiation of cancer stem cells into nontumorigenic progeny could be the major driver of heterogeneity figure 4. Glioblastoma is a devastating form of brain cancer. Introduction on the heterogeneity of tumor cell creative.
As cancer progresses, the tumor begins to consist of more diverse cells with a range of molecular signatures and variable sensitivity to treatment. Reliable information about the coronavirus covid19 is available from the world health organization current situation, international travel. Tumor evolution, heterogeneity, and therapy for our. The onset of acquired resistance to treatment is virtually inevitable in patients with solid tumours. In this short book, he provides readers with a fictional account of how a real, new medical technology could revolutionize the future of medicine by curing with sound. The number of metastatic lesions is closely correlated with prognosis in most cancers. In the past 10 to 15 years, there has been an explosion of information regarding the genesis and pathological classification of and new treatments for brain tumors.
The nci dictionary of cancer terms features 8,594 terms related to cancer and medicine. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. In the future these technologies might inform the selection of targeted combination therapies and enrollment criteria for clinical trials. The clinical and molecular heterogeneity of various cancer types is well documented. A study of tumor heterogeneity in a case with breast cancer. Tumor heterogeneity refers to the difference between genotype and phenotype of tumor. The gombertzian model of tumor growth that many tumors show at the initial stages 5 and becomes absolutely heterogeneous in the late stages is partially a consequence of tumor heterogeneity. On the role of tumor heterogeneity for optimal cancer. Clonal heterogeneity is maintained within tumors clonal frequency does not reflect ability to drive tumor growth multiple drivers within the same tumor limit each others ability to expand eliminating this clonal interference may accelerate progression polyclonal tumors are more likely to metastasize. Two models have been proposed to explain the origin of heterogeneity, the cancer stem cell model and the clonal evolution model. Without question, the presence of tumor heterogeneity has important clinical implications, and at this time, it represents a significant challenge to the success of cancer therapy.
Intratumoral heterogeneity is among the greatest challenges in precision cancer therapy. The tumor microenvironment may also contribute to tumour expansion, as it is capable of altering the selective pressures that the tumour cells are exposed to. Three main types of heterogeneity have been described. Analysis of data from the cancer genome atlas the harvard community has made this article openly available. What are its sources and how does it manifest itself. Symposia have been held on the topic 62, 68, and a new. What have we learned regarding tumor heterogeneity in recent years. Here, the researchers investigate whether a measure of intratumor heterogeneity called mutantallele tumor heterogeneity math is related to mortality death among patients with head and neck squamous cell carcinoma hnscccancers that begin in the cells that line the moist surfaces inside the head and neck, such as cancers of the. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra tumor genetic heterogeneity in breast cancers. Inferring tumor progression from genomic heterogeneity md.
Genetic and epigenetic features of tumor cells vary between both primary tumor and metastases intertumor heterogeneity and in different regions of the same tumor mass intratumor variability. As a result, treatments are now being tailored to an individuals specific cancer subtype, and new therapies are being developed to target the vulnerabilities of different types of cancer cells. Tumor evolution, heterogeneity, and therapy for our patients with. Tumor heterogeneity in breast cancer sunil badve, md, frcpath and yesim go. Addressing tumor molecular heterogeneity using a novel.
Cancer or malignant neoplasia is not any single disease but a name for a group of more than 200 related diseases all characterized by uncontrolled cellular proliferation, invasion and metastasis. However, understanding the heterogeneity of tumours may reveal optimal cancer treatments for patients, reducing the chance of ineffective treatment or relapse. Breast cancer intratumor heterogeneity researchgate. Yihsuan hsiao 1,2, mingchih chou 1, carol fowler 3, jeffrey t. The aim of this study was to clarify the relationship between individual heterogeneity of metastatic tumor sizes and prognosis in patients with multiple pulmonary metastasis of colorectal cancer who received surgical treatment. Intratumor heterogeneity from a cancer stem cell perspective. The main focus of this book is the gliomas, but it also deals with other primary brain tumors, such as meningiomas, as well as brain metastases. Most colorectal cancer occurrences are sporadic, not related to genetic predisposition or family history. The mycn status was investigated by fluorescence in situ hybridization at diagnosis and relapse.
Familial and hereditary tumors recent results in cancer research 1st edition. Several clinical findings can be explained by tumor evolution during progression and metastasis. Multiple types of heterogeneity have been observed between tumour cells, stemming from both genetic and nongenetic variability. In a recent post, philip gerlee highlighted the two biggest contributions of mathematical oncology to cancer research.
Heterogeneity and tumor history cancer darryl shibata what can genomic heterogeneity within a single tumor reveal about the tumors evolution and its diagnosis. Oclcs webjunction has pulled together information and resources to assist library staff as they consider how to handle. Outer radial glialike cancer stem cells contribute to. Heterogeneity of the mycn oncogene in neuroblastoma. Gastroesophageal cancer addressing molecular heterogeneity molecular drivers oncogene addiction interpatient heterogeneity. Tumor biology and microenvironment research national cancer. Singlecell transcriptomic analysis of tumor heterogeneity. Intratumor heterogeneity leads to sampling bias and biomarker failure conor mcauliffe, contributor.
In particular, intratumor heterogeneity ith is closely related to cancer. Heterogeneity of phenotype in breast cancer cell lines intechopen. The heterogeneity of cancer genotypes within a single tumor or between a tumor and metastatic locations can lead to spatial andor temporal sampling bias during tumor. Two of the most widely evoked concepts to explain the origin of. Additional interactions that contribute to the phenotypic heterogeneity of cancer and to the evolutionary history of cellular clones include interactions between individual mutations and the cell of origin in which they arise. Then there is temporal heterogeneity, meaning the genotypic and phenotypic characteristics of the cancer cells change with time. One mechanism to explain tumor heterogeneity and differences in tumor behavior is the accumulation of many kinds of dna changes mutations in the genome of cancer cells over time. A study of tumor heterogeneity in a case with breast. Intertumor heterogeneity exceeds the boundaries of specific tumors and also of their molecular classifications 1, 2, which makes the clinical approach very complex. The evolutionary history of lethal metastatic prostate cancer. Clonal history and genetic predictors of transformation into smallcell carcinomas from lung. Tumor heterogeneity predicts metastatic potential in. About frontiers institutional membership books news frontiers.
In this study, we compared mutations in paired primary and metastatic colorectal cancer tumor samples to determine whether tumor heterogeneity can predict tumor metastasis. May 20, 2014 in recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Intratumor genetic heterogeneity and mortality in head. We herein report a case of metastatic breast cancer indicated tumor heterogeneity by clinical findings and a genomic analysis. Implications of tumor heterogeneity on biomarkerdirected therapy. Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Conversely, if genetic heterogeneity is extensive, every tumorigenic cell could form a genetically distinct tumor rather than recapitulating the tumor from which it derives. The process of metastasis is highly selective, and the metastatic lesion represents the end point of many destructive events that only a few cells can survive.
We offer a widget that you can add to your website to let users look up cancerrelated terms. The role of tumour heterogeneity and clonal cooperativity in. Tumour heterogeneity and cancer cell plasticity nature. Tumour heterogeneity refers to the existence of subpopulations of cells, with distinct genotypes and phenotypes that may harbour divergent biological behaviours, within a primary tumour and its metastases, or between tumours of the same histopathological subtype intra and intertumour, respectively. Tumorintrinsic drivers of heterogeneity upper left include diversity in. Breast cancer intratumor heterogeneity breast cancer. Recent progress in molecular biology, biological chemistry, im munology, and other disciplines has now. Within the main tumor mass as well as among and within metastases, different subclones might have evolved carrying a diverse mutational burden thus reflecting the.
The development of a metastasis is dependent on an interplay between host factors and intrinsic characteristics of malignant tumor cells. Institute of medicine, chung shan medical university, taiwan 2. Nov 25, 2014 past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. The rapidly changing landscape of oncology has brought new light, and with it, new challenges to optimizing therapeutic strategies for patients. Department of obstetrics and gynecology, changhua christian hospital, taiwan 3. Review breast cancer intra tumor heterogeneity luciano g martelotto, charlotte ky ng, salvatore piscuoglio, britta weigelt and jorge s reisfilho abstract in recent years it has become clear. Tumour heterogeneity an overview sciencedirect topics. A 64yearold woman with advanced breast cancer was treated with primary chemotherapy. Genomic classification of tumors center for cancer research.
Tumor heterogeneity and the biology of cancer invasion and. While it is current practice today to molecularly characterize tumors based on their genetic fingerprints, ccr investigators were among the first to classify tumors based on genetics. Toward understanding and exploiting tumor heterogeneity. Is there a standard reference for the importance of tumor. In the era of precision oncology whereby molecular profiling of tumors is incorporated into clinical care, both intra and intertumoral molecular and genetic heterogeneity have been described. Fluorescence in situ hybridization with signal detection on the singlecell level allows a critical judgement of mycn intratumoral heterogeneity. I could homogenous a sample of the tumor, separate it into 3 parts and test against a panel of drugs. This phenomenon occurs both between tumours intertumour heterogeneity and within tumours intra. Then you can start reading kindle books on your smartphone, tablet, or computer. Tumor heterogeneity in a follicular carcinoma of thyroid. Impact of tumor and immunological heterogeneity on the.
In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Tumour heterogeneity and resistance to cancer therapies. Tumor heterogeneity has been suggested based on clinical and pathological findings. Although the involvement of intratumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Evaluating tumor heterogeneity in immunohistochemistry. Both intertumor and intratumor heterogeneity have crucial. Breast cancer is a heterogeneous disease and differs greatly among different patients intertumor heterogeneity and even within each individual tumor intratumor heterogeneity. Colon cancer is the third most common cancer worldwide.
The metastatic spread of malignant tumours remains as one of the most intractable problems in clinical oncology. Heterogeneity in the expression of established prognostic and predictive. The latter includes phenotypic diversity such as cell surface markers, epigenetic abnormality, growth rate, apoptosis and other hallmarks of cancer that. I worked in a research lab that was trying to do drug sensitivity testing on patients tumors. For clinicians, the main challenge is the socalled intratumor heterogeneity. For the first point, the standard historical reference is. Not only tumor but also therapy heterogeneity annals of. Burgeoning genetic, epigenetic and phenomenological data support the existence of intratumor genetic heterogeneity in breast cancers. Patient derived tumor xenograft models 1st edition. Cancer is a disease characterized by high genetic heterogeneity, driven by the multiple aberration events that occur in cancer cells over time and that are caused by high genomic instability, a. Cancer heterogeneity, long recognized as an important clinical determinant of patient outcomes, was poorly understood at a molecular level. Within a tumor, there is diversity in tumor cell proliferation, immune infiltration, differentiation status, and necrosis that. Experimental analysis of this phenomenon is fuelled by the hope that a more complete understanding of the process will give rise to insights allowing the eventual development of novel and successful therapeutic interventions. Intratumor heterogeneity in breast cancer has limited impact.
Tumor morphologic heterogeneity has long been recognized by pathologists and forms the basis of many tumor grading prognostic classification systems. The heterogeneity of breast tumors and their changes in disease relapse represent a formidable challenge of successful cancer treatment. Tumor heterogeneityan intriguing concept cancer or malignant neoplasia is not any single disease but a name for a group of more than 200 related diseases all characterized by uncontrolled cellular proliferation, invasion and metastasis. Numerous and frequentlyupdated resource results are available from this search. Genomic and transcriptomic heterogeneity in metaplastic. They aim to illuminate how the variety of cell types in a tumor influences cancer progression, and to predict the most effective course of treatment for a given tumor. The complexity of tumor heterogeneity and the emergence of resistance to therapy.
Genomic studies have significantly improved our understanding of heterogeneity, and have pointed to ways in which heterogeneity might be understood and defeated for therapeutic effect. It appears to be different in every single patient and continuously keeps evolving into a progressively more. The existence of subpopulations of cells in cancers with increased tumor initiating capacities and selfrenewal potential, often termed cancer stem cells, is a much discussed and key area of cancer biology. Recently, there is an increasing interest to quantify the tumor heterogeneity from molecular images, especially, pet, as the tumor heterogeneity is an important biomarker for aggressiveness and. This may be related to host factors, such as tumor microenvironment and germline. Nov 29, 2017 intra tumor heterogeneity in transcriptomic grade. Clinical and morphologic intertumor heterogeneity is reflected by staging systems and histopathologic classification of breast cancer. Tumour heterogeneity describes the observation that different tumour cells can show distinct. To get a handle on cancers heterogeneity, some researchers are using computational modeling and simulation. That tumor heterogeneity itself is an area suitable for experimental and clinical investigation has not been widely appreciated.
Jun 23, 2009 the results of our recent studies investigating breast cancer cells with stem cell characteristics and the genetic diversity of cellular populations within tumors imply multiple layers of heterogeneity and a combination of different molecular mechanisms underlying breast tumor heterogeneity. Phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental differences and reversible changes in cell properties. Overview on clinical relevance of intratumor heterogeneity. Phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental. Because what kills one kind of cell might pass over another, we need treatments in combination or in sequence, working in different ways, that together may eliminate all of the cancer. When a cell divides to form two new cells, its dna needs to be replicated or doubled to enable distribution over two daughter cells. Tumor heterogeneity and lesionspecific response to targeted therapy in colorectal cancer. Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. Cellular heterogeneity is a wellrecognized attribute of both normal and neoplastic tissue.
The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. If a tumor consists of a homogeneous population of chemotherapeutically sensitive cells, then optimal protocols consist of upfront dosing of cytotoxic agents at. Such cellular heterogeneity is very important due to its impact on therapy and especially states of treatment resistance. To identify aspects of tumor heterogeneity that may illuminate drivers of tumor invasion, we created a glioblastoma tumor cell atlas with singlecell transcriptomics of cancer cells mapped onto a reference framework of the developing and adult human brain. Tumor heterogeneity and implications for clinical practice. This phenomenon occurs both between tumours intertumour heterogeneity and within tumours intratumour heterogeneity. It should be possible to infer the past by characterizing mutations in different parts of the same tumor. Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Promise, potential and practice offers guidance on how to conduct pdx modeling and trials, including how to know when these models are appropriate for use, and how the data should be interpreted through the selection of immunodeficient strains. Such cancer cell diversityrepresented by the red stars, blue circles, and green triangles in this illustrationis called tumor heterogeneity. Tumour cell heterogeneity and the biology of metastasis.
Despite the major clinical and intellectual advances that have resulted from studying. Tumor heterogeneity is an inherent outcome of branching cell division, with the amount of genomic heterogeneity dependent on the time after transformation and how cancer cells divide and migrate. It appears to be different in every single patient and continuously keeps evolving into a progressively. Definition of heterogeneous nci dictionary of cancer terms. Mycn amplification is an important therapystratifying marker in neuroblastoma. The most wellknown is interpatient tumor heterogeneity, wherein no two patients with the same subtype of tumor behave the same clinically, with or without treatment. Transcriptomic grade tg is a reproducible method to divide primary breast tumors into high and low grade based on gene expression and thereby eliminate classification of tumors as intermediategrade.
This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitnesspromoting mutations conferring a malignant cellular phenotype. Intratumor heterogeneity leads to sampling bias and. Then we discuss the research value of genetic diversity in the evolutionary history of human individual tumor, introduce the two modes of the genetic heterogeneity. There are several types of genetic heterogeneity in cancer biology. Frontiers tumor heterogeneity in breast cancer medicine. Breast tumor heterogeneity has been noted in histology and clinical outcome for a long time, and these differences have served as the basis for disease classification. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic. Schilsky 1 clinical oncologists have long recognized the great variability in the cellular morphol ogy, natural history, and response to ther apy of human tumors. Tumor heterogeneity and therapeutic resistance american.
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