Intratumor heterogeneity is a major obstacle toward understanding and treatment of cancers. We have analyzed cellular genetic and phenotypic heterogeneity in breast tumors and found that higher pre-treatment genetic diversity predicts therapy resistance and distant metastases are the most diverse. We also developed an experimental model of clonal heterogeneity and shown that polyclonal tumors grow faster and are more metastatic, the tumor-driver clone can be a minor subpopulation acting via non-cell-autonomous mechanisms, a dominant clone can outcompete the tumor-driver minor clone leading to tumor collapse, and that cancer therapies intensify clonal competition potentially leading to inadvertent acceleration of disease progression.
Please take this quick survey to tell us about what happens after you publish a paper. Clinical and Translational Oncology. Cancer progression is a dynamic process of clonal adaptation to changing microenvironments.
Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Heterogeneity is evident between cancers from different patients inter-tumor heterogeneity and within a single tumor intra-tumor heterogeneity. The latter includes phenotypic diversity such as cell surface markers, epi genetic abnormality, growth rate, apoptosis and other hallmarks of cancer that eventually drive disease progression and treatment failure.
Even with the identical clinicopathological features, the ability for metastasis is vastly different among triple-negative breast cancer TNBC patients. Intratumor heterogeneity ITHwhich is common in breast cancer, may be a key mechanism leading to the tumor progression. However, the presence of regional heterogeneity did not correlate with metastasis or MFS.
The mammary gland distinguishes itself from other organs since much of its development occurs after birth, allowing for adult developmental studies. Postnatal development of the mammary gland comprises stages of ductal morphogenesis, alveologenesis, lactation and involution, and is regulated by a complex interplay of systemic hormones notably estrogen, progesterone and prolactin and local growth factors. The observation that the mammary gland exhibits plasticity through multiple cycles of pregnancy, lactation and involution, accompanied by dynamic changes in proliferation, differentiation, cell death and tissue remodeling, suggested that there exists a renewable stem or progenitor cell population underlying these processes.
The attempts to identify, isolate and characterize cancer stem cell populations are mostly dependent on cell-surface markers. In breast cancer, several putative breast cancer stem cell BCSC markers have already been reported, but the agreement on their phenotypic characterization is still absent. In fact, it became unfeasible to obtain a universal combination of markers that could specifically identify BCSCs in all cases of breast cancer.
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In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra-tumor genetic heterogeneity in breast cancers; however, its basis is yet to be fully defined. Two of the most widely evoked concepts to explain the origin of heterogeneity within tumors are the cancer stem cell hypothesis and the clonal evolution model. Although the cancer stem cell model appeared to provide an explanation for the variability among the neoplastic cells within a given cancer, advances in massively parallel sequencing have provided several lines of evidence to suggest that intra-tumor genetic heterogeneity likely plays a fundamental role in the phenotypic heterogeneity observed in cancers.
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. A minimal level of intra-tumour heterogeneity is a simple consequence of the imperfection of DNA replication : whenever a cell normal or cancerous divides, a few mutations are acquired  —leading to a diverse population of cancer cells. However, research into understanding and characterizing heterogeneity can allow for a better understanding of the causes and progression of disease.