Krasmutant lung adenocarcinomas, accounting for 30% of nonsmall cell lung cancers, exhibit a high level of heterogeneity with emerging clinical significance 1. The selection of fitter subclones in the context of tumor evolution was postulated by nowell in the 1970s. Breast cancer is a heterogeneous group of neoplasms originating from the epithelial cells lining the milk ducts. If you use it in your talks, put my name on the slide. Genomic analyses can be used to dissect the heterogeneity of breast cancer. While tumor heterogeneity can be influenced by genetic and or epigenetic alterations cooccurring with kras, heterogeneous tumor subsets can also be the product of differing cellsoforigin 2. 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.
Heterogeneity can manifest spatially, reflecting differences in the composition of the primary tumor and tumors at secondary sites or across regions of the same tumor mass and temporally, at different time points across a tumor s natural history. The models are not mutually exclusive, and it is believed that they both contribute to heterogeneity in varying amounts across different tumour types. Both methods illustrate the potential for decreasing etiologic heterogeneity that large, populationbased multisource databases can provide. However, the significance of tumor heterogeneity on disease course and clinical outcome in bladder cancer is of more recent interest to researchers and clinicians. Breast cancer intratumor genetic heterogeneity medscape. Tumoral heterogeneity of breast cancer request pdf. Identifying rule books of cancer evolution might have important implications for. Dissection of breast cancer heterogeneity by using intr openi.
The following narrative describes over 100 years of aacr history. Heterogeneity of small cell lung cancer stem cells request pdf. When cancer spreads through the blood, it may spread through the body but is more likely to travel to certain areas depending on the cancer type. Breast cancers are heterogeneous both in their molecular features and clinical. These subclonal populations of cells will expand or regress in response to the selective pressures exerted by the tumor microenvironment and cancerdirected treatment 1, 2. This connection might be responsible for tumor heterogeneity, progression, and acquired resistance to therapy, followed by disease recurrence 40, 41, 43. 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. Once prostate cancer has spread to other areas of the body, it may still respond to treatment and may be controlled, but its unlikely to be cured. Intratumor heterogeneity predicts metastasis of triple. Tumor heterogeneity has been recognized in many cancer types for decades.
Such cellular heterogeneity is very important due to its impact on therapy and especially states of treatment resistance. Because of their reversibility, epigenetic modifications likely allow dynamic switching from a silent state to growth and invasiveness, respectively, and could thus also contribute to intra tumor heterogeneity or differences between primary tumors and their metastases. Pancancer analysis of intratumor heterogeneity as a. Jun 05, 2014 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. It is becoming increasingly evident that intratumor genetic heterogeneity is one of. Nuclear pleomorphism is another example of intratumour heterogeneity, which is accounted for in breast cancer grading. Sep 29, 2016 tumor heterogeneity has been suggested based on clinical and pathological findings. A tumor is a heterogeneous population of cells, containing transformed cancer cells, supportive cells and tumor infiltrating cells. New book by asu researcher explores cancers pervasive. The role of tumour heterogeneity and clonal cooperativity in. A minimal level of intratumour heterogeneity is a simple consequence of the imperfection of dna replication. Resolving the spatial and temporal heterogeneity of subclones with cancer driver events may offer insight into therapy response, tumor evolutionary histories and clinical trial design.
Host genetics and the tumor microenvironment impact on tumor. Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer. Jun, 2017 the wideranging text covers the genetics of cancer populations, genetic diversity within tumors intratumor heterogeneity, the expansion of mutant clones, cancer stem cells in the dynamics of tumors, the evolution of metastasis, and techniques for improving cancer therapy through monitoring cancers evolutionary response to treatment. Cancer can spread from its original site by local spread, lymphatic spread to regional lymph nodes or by hematogenous spread via the blood to distant sites, known as metastasis. Tumor heterogeneity in cancer drug response, resistance, and relapse symposium 2014. Aug 27, 2014 the presence of multiple subclones within tumors mandates understanding of longitudinal and spatial subclonal dynamics. Such intratumor heterogeneity ith poses significant clinical challenges, including formulation of optimal biopsy strategy, characterization of molecular. Cancer genomes are formed by evolutionary processes within each patient.
In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is. Every persons cancer develops and grows in its own way and is unique in terms of what therapies its sensitive to. Tumor heterogeneity has been found in virtually all types of cancer, and. Elusive dream describes some answers of achieving the so far elusive dream of treating cancers like other chronic diseases with therapies that focus using improved drug delivery systems designed to better align with the unique biological and physiological properties of cancer. Molecular basis of tumor heterogeneity in endometrial. Phenotypic and functional heterogeneity arise among cancer cells within the same tumor as a consequence of genetic change, environmental differences, and reversible changes in cellular properties. The studies of last decades have shown a link between cancer stem cell formation and the process of epithelialmesenchymal transition. Some cancers also contain a hierarchy in which tumorigenic cancer stem cells differentiate into nontumorigenic progeny. The heterogeneity of cancer metabolism anne le springer. Special issue metastatic progression and tumour heterogeneity. Our results suggest pedigreeinformed tumor phenotypes can map genes for breast cancer, and that various different cancer pleiotropies exist for highrisk breast cancer pedigrees.
Patient derived tumor xenograft models 1st edition. These are the cancer stem cell model and the clonal evolution model. The cancer stem cell model provides one explanation for the phenotypic and functional heterogeneity among cancer cells in some tumors. Feb 26, 2019 as cancer progresses, the tumor begins to consist of more diverse cells with a range of molecular signatures and variable sensitivity to treatment. We herein report a case of metastatic breast cancer indicated tumor heterogeneity by clinical findings and a genomic analysis. Sep 19, 20 phenotypic and functional heterogeneity arise among cancer cells within the same tumor as a consequence of genetic change, environmental differences, and reversible changes in cellular properties. According to a mouse model, recurrence of a primary tumor demands multiple propensities for each clone, such as invasion, local dissemination, vascular embolus, circulating tumor cells, and micrometastasis. It is becoming increasingly evident that intratumor genetic heterogeneity is. Recent approaches encompassing the phenotypic cell. A 64yearold woman with advanced breast cancer was treated with primary chemotherapy.
Intratumoral genetic heterogeneity of driver somatic mutations is present in a variety of tumor types, yet the extent of heterogeneity is variable. Erica jackson, genentech, describes enrichment of cells with stem cell markers in populations of lung cancer cells. Tumor heterogeneity in cancer drug response, resistance, and relapse dr. Intratumor heterogeneity from a cancer stem cell perspective. The clinical and molecular heterogeneity of various cancer types is well documented. 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. In addition to metastatic deposits, routine serial monitoring of breast cancer heterogeneity during disease progression or in response to treatment in ctcs, dtcs, and or ctdna shows great promise for overcoming sampling bias when only a limited number of biopsies are available from the primary tumor or metastases. Tumour heterogeneity describes the observation that different tumour cells can show distinct.
Both prostate cancer and its treatment can cause urinary incontinence. Dear colleagues, intratumoral heterogeneity is one of the biggest current challenges for cancer therapy. This tumor heterogeneity gives a selective advantage to the best fit clonal and subclonal cells of a tumor. Heterogeneity of small cell lung cancer stem cells. Intratumor heterogeneity may foster the selection of a resistant subclone.
A study of tumor heterogeneity in a case with breast cancer. 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. Prostate cancer that spreads to the bones can cause pain and broken bones. During the course of disease, cancers generally become more heterogeneous. Tumour heterogeneity and resistance to cancer therapies. Due to the heterogeneity and the unchecked proliferation of tumor cells, cancer is given a selective advantage not only over noncancerous cells, but also against selective pressures that choose against it, such as pharmaceutical and. It is also readily apparent to those clinicians treating cancer that there is marked variation in tumour behaviour between patients with the same tumour type. As a result of this heterogeneity, the bulk tumour might include a diverse collection of. From the simple beginning of a few scientists gathering to share information to the multifaceted organization that exists today, the growth of the aacr reflects the increasing complexity of our understanding of over 200 diseases we. In addition to genetics, epigenetic mechanisms are crucial players in tumorigenesis. At memorial sloan kettering and at other research centers around the world, the push is on to characterize the molecular variations between tumors known as intertumor heterogeneity and offer individualized treatments to more patients. This phenomenon occurs both between tumours and within tumours. Genetic heterogeneity of tumors is rooted in one of the key hallmarks of. Although tumor heterogeneity is widely accepted, the existence of cancer stem cells cscs and their proposed role in tumor maintenance has always been challenged and remains a matter of debate.
Malignant cells can continue to evolve during cancer development and progression, often leading to the generation of genetically and or phenotypically distinct clones within the same tumor. This intra tumor heterogeneity is further enhanced by clonal variation and microenvironmental influences on cancer cells, which also do not represent a homogeneous set of cells. Backgroundamong patients with nonsmallcell lung cancer nsclc, data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. Tracking the evolution of nonsmallcell lung cancer nejm. To get a handle on cancers heterogeneity, some researchers are using computational modeling and simulation. Several clinical findings can be explained by tumor evolution during progression and metastasis. Altogether, the repertoire of admixed clonal and subclonal populations is referred to as intratumor genetic heterogeneity ith. Ecs is a clinically aggressive, highgrade, metaplastic carcinoma. Tumor heterogeneity and cancer cell plasticity ncbi. Namely, epithelial cells undergoing emt acquire csc. We use an integrated analysis of breast cancer that combines independent methods of genomic analyses to highlight the complexity of signaling pathways underlying different breast cancer phenotypes and to identify optimal therapeutic opportunities. This book provides, all in one resource, the most recent data on bone cancer development cellular and molecular mechanisms, genomic and proteomic analyses, clinical analyses histopathology, imaging, pain monitoring, as well as new therapeutic approaches and clinical trials for primary bone tumors and bone metastases. Endometrial carcinosarcoma ecs represents one of the most extreme examples of tumor heterogeneity among human cancers. 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.
At the morphological level, intratumor heterogeneity in ecs is due to an admixture of epithelial carcinoma and mesenchymal sarcoma components that can include heterologous tissues, such as skeletal muscle. 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. What you need to know about cancers history, treatment, and prevention bollinger, ty m. As a result of this heterogeneity, the bulk tumour might include a diverse collection of cells harbouring distinct molecular signatures with differential levels of sensitivity to treatment. Alternative cellsoforigin influence the heterogeneity of. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. Understanding tumour evolution and metastasis could yield novel. Cancer is one of the leading causes of morbidity and mortality worldwide, with. Deciphering intratumor heterogeneity and temporal acquisition. However, exciting recent developments in singlecell omics, cellular tracking, and imaging, alongside the expansion of new tools to study clonal and phenotypic diversity in patient samplessuch as pdxs, organoids, and liquid biopsiesenable a deeper understanding of the heterogeneous. There are two models used to explain the heterogeneity of tumour cells. The challenges of tumor genetic diversity mroz 2017.
Charting the evolutionary history of individual tumours has revealed. Together, they impact patient treatment and outcomes. As cancer progresses, the tumor begins to consist of more diverse cells with a range of molecular signatures and variable sensitivity to treatment. By the time of diagnosis, breast cancers are composed of heterogeneous populations of tumor cells. Cancer evolution is a stepwise process of mutations and clonal expansions. Tumour heterogeneity and cancer cell plasticity nature. Considering the fate of cancer cells, a malignant cell will meet and surpass various pressures during cancer progression. Family study designs informed by tumor heterogeneity and. 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.
966 188 1492 67 575 178 1052 1488 1018 1070 876 713 382 826 600 1384 1408 898 700 1241 491 899 233 584 136 691 403 1460 1043 1010 747 595 389 627 1306 679 1401 720 320 313 239 242 489 411 1005 993 1189