Molecular aspects of early stages of breast cancer progression (original) (raw)

Phenotypic Heterogeneity in Tumor Progression, and Its Possible Role in the Onset of Cancer

Frontiers in Genetics

Heterogeneity among isogenic cells/individuals has been known for at least 150 years. Even Mendel, working on pea plants, realized that not all tall plants were identical. However, Mendel was more interested in the discontinuous variation between genetically distinct individuals. The concept of environment dictating distinct phenotypes among isogenic individuals has since been shown to impact the evolution of populations in numerous examples at different scales of life. In this review, we discuss how phenotypic heterogeneity and its evolutionary implications exist at all levels of life, from viruses to mammals. In particular, we discuss how a particular disease condition (cancer) is impacted by heterogeneity among isogenic cells, and propose a potential role that phenotypic heterogeneity might play toward the onset of the disease.

Cancer heterogeneity: converting a limitation into a source of biologic information

Journal of Translational Medicine, 2017

Analysis of spatial and temporal genetic heterogeneity in human cancers has revealed that somatic cancer evolution in most cancers is not a simple linear process composed of a few sequential steps of mutation acquisitions and clonal expansions. Parallel evolution has been observed in many early human cancers resulting in genetic heterogeneity as well as multilineage progression. Moreover, aneuploidy as well as structural chromosomal aberrations seems to be acquired in a non-linear, punctuated mode where most aberrations occur at early stages of somatic cancer evolution. At later stages, the cancer genomes seem to get stabilized and acquire only few additional rearrangements. While parallel evolution suggests positive selection of driver mutations at early stages of somatic cancer evolution, stabilization of structural aberrations at later stages suggests that negative selection takes effect when cancer cells progressively lose their tolerance towards additional mutation acquisition. Mixing of genetically heterogeneous subclones in cancer samples reduces sensitivity of mutation detection. Moreover, driver mutations present only in a fraction of cancer cells are more likely to be mistaken for passenger mutations. Therefore, genetic heterogeneity may be considered a limitation negatively affecting detection sensitivity of driver mutations. On the other hand, identification of subclones and subclone lineages in human cancers may lead to a more profound understanding of the selective forces which shape somatic cancer evolution in human cancers. Identification of parallel evolution by analyzing spatial heterogeneity may hint to driver mutations which might represent additional therapeutic targets besides driver mutations present in a monoclonal state. Likewise, stabilization of cancer genomes which can be identified by analyzing temporal genetic heterogeneity might hint to genes and pathways which have become essential for survival of cancer cell lineages at later stages of cancer evolution. These genes and pathways might also constitute patient specific therapeutic targets.

Tumour heterogeneity: principles and practical consequences

Virchows Archiv : an international journal of pathology, 2016

Two major reasons compel us to study tumour heterogeneity: firstly, it represents the basis of acquired therapy resistance, and secondly, it may be one of the major sources of the low level of reproducibility in clinical cancer research. The present review focuses on the heterogeneity of neoplastic disease, both within the primary tumour and between primary tumour and metastases. We discuss different levels of heterogeneity and the current understanding of the phenomenon, as well as imminent developments relevant for clinical research and diagnostic pathology. It is necessary to develop new tools to study heterogeneity and new biomarkers for heterogeneity. Established and new in situ methods will be very useful. In future studies, not only clonal heterogeneity needs to be addressed but also non-clonal phenotypic heterogeneity which might be important for therapy resistance. We also review heterogeneity established in major tumour types, in order to explore potential similarities tha...

Cancer heterogeneity--a multifaceted view

EMBO reports, 2013

Cancers of various organs have been categorized into distinct subtypes after increasingly sophisticated taxonomies. Additionally, within a seemingly homogeneous subclass, individual cancers contain diverse tumour cell populations that vary in important cancer-specific traits such as clonogenicity and invasive potential. Differences that exist between and within a given tumour type have hampered significantly both the proper selection of patients that might benefit from therapy, as well as the development of new targeted agents. In this review, we discuss the differences associated with organ-specific cancer subtypes and the factors that contribute to intra-tumour heterogeneity. It is of utmost importance to understand the biological causes that distinguish tumours as well as distinct tumour cell populations within malignancies, as these will ultimately point the way to more rational anti-cancer treatments.

Host-Mediated Induction of Tumor Heterogeneity

Annals of the New York Academy of Sciences, 1989

Tumor heterogeneity, that is, the existence within single neoplasms of clonal tumor cell subpopulations of diverse phenotype, has been the subject of intense investigation over the past 10-15 years. It has been demonstrated, repeatedly, that one can isolate tumor subpopulations that differ in behavioral characteristics, such as growth rate, sensitivity to treatment, immunogenicity and ability to metastasize, as well as subpopulations that differ in molecular, genetic, and biochemical characteristics, such as karyotype, production of various growth factors or other mediators, and expression of marker antigens or receptors."' Depending upon the phenotype, it has also been possible to demonstrate heterogeneous tumor populations within tissue pieces or suspensions of whole tumors. These evidences of tumor cell diversity, as well as the generally accepted tenet that most cancers are clonal in origin,) have raised the question of the source of tumor cell divergence.

Assessing genetic markers of tumour progression in the context of intratumour heterogeneity

Cytometry, 1998

This is a report from the Kananaskis working group on quantitative methods in tumour heterogeneity. Tumour progression is currently believed to result from genetic instability and consequent acquisition of new genetic properties in some of the tumour cells. Cross-sectional assessment of genetic markers for human tumours requires quantifiable measures of intratumour heterogeneity for each parameter or characteristic observed; the relevance of heterogeneity to tumour progression can best be ascertained by repeated assessment along a tumour progressional time line. This paper outlines experimental and analytic considerations that, with repeated use, should lead to a better understanding of tumour heterogeneity, and hence, to improvements in patient diagnosis and therapy. Four general principles were agreed upon at the Symposium: (1) the concept of heterogeneity requires a quantifiable definition so that it can be assessed repeatably; (2) the quantification of heterogeneity is necessary so that testable hypotheses may be formulated and checked to determine the degree of support from observed data; (3) it is necessary to consider (a) what is being measured, (b) what is currently measurable, and (c) what should be measured; and (4) the proposal of working models is a useful step that will assist our understanding of the origins and significance of heterogeneity in tumours. The properties of these models should then be studied so that hypotheses may be refined and validated. Cytometry 31:67-73, 1998.

Tumor heterogeneity in neoplasms of breast, colon, and skin

BMC Research Notes, 2010

Background: Different cell subpopulations in a single tumor may show diverse capacities for growth, differentiation, metastasis formation, and sensitivity to treatments. Thus, heterogeneity is an important feature of tumors. However, due to limitations in experimental and analytical techniques, tumor heterogeneity has rarely been studied in detail.