Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledge-based therapies directed against specific oncogenic signaling targets. These therapies often ...induce dramatic responses in susceptible tumors. Unfortunately, most advanced cancers, including those with robust initial responses, eventually acquire resistance to targeted therapies and relapse. Even though immune-based therapies are more likely to achieve complete cures, acquired resistance remains an obstacle to their success as well. Acquired resistance is the direct consequence of pre-existing intratumor heterogeneity and ongoing diversification during therapy, which enables some tumor cells to survive treatment and facilitates the development of new therapy-resistant phenotypes. In this review, we discuss the sources of intratumor heterogeneity and approaches to capture and account for it during clinical decision making. Finally, we outline potential strategies to improve therapeutic outcomes by directly targeting intratumor heterogeneity.
Tumors are composed of millions of cancer cells embedded in a microenvironment distorted by neoplastic changes. The startling heterogeneity of both cancer cells and cells composing the tumor microenvironment fuels disease progression and treatment resistance. Thus, better understanding of cellular, molecular, and spatial heterogeneity within tumors and the application of this knowledge for treatment design are essential for improving clinical outcomes. In this review we summarize sources of intratumor heterogeneity (ITH), methods to quantitatively assess ITH, and its clinical relevance. Although most of the points discussed are applicable to all types of cancers, some, such as spatial and microenvironmental heterogeneity, are more relevant to solid tumors, which represent our main focus.
Transitions between epithelial and mesenchymal states have crucial roles in embryonic development. Emerging data suggest a role for these processes in regulating cellular plasticity in normal adult ...tissues and in tumours, where they can generate multiple, distinct cellular subpopulations contributing to intratumoural heterogeneity. Some of these subpopulations may exhibit more differentiated features, whereas others have characteristics of stem cells. Owing to the importance of these tumour-associated phenotypes in metastasis and cancer-related mortality, targeting the products of such cellular plasticity is an attractive but challenging approach that is likely to lead to improved clinical management of cancer patients.
Intratumor heterogeneity represents a major obstacle to effective cancer treatment and personalized medicine. However, investigators are now elucidating intratumor heterogeneity at the single-cell ...level due to improvements in technologies. Better understanding of the composition of tumors, and monitoring changes in cell populations during disease progression and treatment, will improve cancer diagnosis and therapeutic design. Measurements of intratumor heterogeneity may also be used as biomarkers to predict the risk of progression and therapeutic resistance. We summarize important considerations related to intratumor heterogeneity during tumor evolution. We also discuss experimental approaches that are commonly used to infer intratumor heterogeneity and describe how these methodologies can be translated into clinical practice.
Heterogeneity in breast cancer Polyak, Kornelia
The Journal of clinical investigation,
10/2011, Letnik:
121, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Breast cancer is a heterogeneous disease. There is a high degree of diversity between and within tumors as well as among cancer-bearing individuals, and all of these factors together determine the ...risk of disease progression and therapeutic resistance. Advances in technologies such as whole-genome sequencing and functional viability screens now allow us to analyze tumors at unprecedented depths. However, translating this increasing knowledge into clinical practice remains a challenge in part due to tumor evolution driven by the diversity of cancer cell populations and their microenvironment. The articles in this Review series discuss recent advances in our understanding of breast tumor heterogeneity, therapies tailored based on this knowledge, and future ways of assessing and treating heterogeneous tumors.
Cancer is a disease of genes. Inherited or somatic alterations in genes are what make a normal cell ignore growth-controlling signals and form a tumor that eventually leads to the destruction of the ...organism. Based on accumulated knowledge on the genetic composition of cancer cells, the clonal evolution model of tumorigenesis was established, which explains multiple aspects of human disease and clinical observations. However, the recently popularized cancer stem cell hypothesis questions that all or most tumor cells can participate in tumor evolution and restricts this property to a subset of them defined as 'cancer stem cells' due to their stem cell-like characteristics. Enthusiasm surrounding this area of investigation and its presumed clinical implications led to a spurt of studies in various cancer types and model systems. Rigorous study design and critical data interpretation have to be employed to test the scientific and clinical relevance of the cancer stem cell hypothesis and its relationship to the clonal evolution model.
Human tumors often display startling intratumor heterogeneity in various features including histology, gene expression, genotype, and metastatic and proliferative potential. This phenotypic and ...genetic heterogeneity plays an important role in neoplasia, cancer progression, and therapeutic resistance. In this issue of the journal (beginning on page 1388), Merlo et al. report their use of molecular data from 239 patients with Barrett's esophagus to evaluate the propensity of major diversity indices for predicting progression to esophageal adenocarcinoma. This work helps elucidate the implications of molecular heterogeneity for the evolution of neoplasia.
Epigenetic regulators are emerging therapeutic targets in a wide variety of human cancers. BET bromodomain proteins have been identified as key regulators of oncogenic transcription factors including ...MYC; therefore, their inhibition might provide a way to block these "undruggable" targets. Several BET bromodomain inhibitors are in clinical development with promising preliminary findings. However, tumors acquire resistance to these agents in several different ways. In this review, we summarize the role that BET bromodomain proteins play in tumorigenesis as well as the molecular mechanisms underlying therapeutic responses and resistance to their inhibition with emphasis on BRD4 and breast cancer.
Breast cancer comprises a heterogeneous group of malignancies derived from the ductal epithelium. The microenvironment of these cancers is now recognized as a critical participant in tumor ...progression and therapeutic responses. Recent data demonstrate significant gene expression and epigenetic alterations in cells composing the microenvironment during disease progression, which can be explored as biomarkers and targets for therapy. Indeed, gene expression signatures derived from tumor stroma have been linked to clinical outcomes. There is increasing interest in translating our current understanding of the tumor microenvironment to the development of novel therapies.
Breast tumors are composed of a variety of cell types with distinct morphologies and behaviors. It is not clear how this tumor heterogeneity comes about. Two popular concepts that attempt to explain ...this are the cancer stem cell hypothesis and the clonal evolution model. Each of these ideas has been investigated for some time, leading to the accumulation of numerous findings that are used to support one or the other. Although the two views share some similarities, they are fundamentally different notions with very different clinical implications. Analysis of the research backing each concept, along with a review of the results of our recent study investigating putative breast cancer stem cells, suggests how the cancer stem cell hypothesis and the clonal evolution model may be involved in generating breast tumor heterogeneity. An understanding of this process will allow the development of more effective ways to treat and prevent breast cancer.
Centrosome amplification has long been recognized as a feature of human tumours; however, its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed ...cells and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumours, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumour progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behaviour is similar to that induced by overexpression of the breast cancer oncogene ERBB2 (ref. 4) and indeed enhances invasiveness triggered by ERBB2. Our data indicate that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.
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