The Origins and Implications of Intratumor Heterogeneity

Michor, Franziska; Polyák, Kornélia

doi:10.1158/1940-6207.capr-10-0234

Cited by 187 publications

(164 citation statements)

References 26 publications

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“…In yeast, HSP90, an important regulatory target of HSF1, potentiates the emergence of drug resistance by enabling the generation of greater phenotypic diversity (22). In human cancer, the general role of diversity in progression is less well-understood, but early data are intriguing (23). For example, in Barrett's esophagus, greater diversity in genetic and epigenetic parameters is associated with progression to invasive cancer (24).…”

Section: Discussionmentioning

confidence: 99%

High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

Santagata

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

274

273

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Heat-shock factor 1 (HSF1) is the master transcriptional regulator of the cellular response to heat and a wide variety of other stressors. We previously reported that HSF1 promotes the survival and proliferation of malignant cells. At this time, however, the clinical and prognostic significance of HSF1 in cancer is unknown. To address this issue breast cancer samples from 1,841 participants in the Nurses' Health Study were scored for levels of nuclear HSF1. Associations of HSF1 status with clinical parameters and survival outcomes were investigated by Kaplan-Meier analysis and Cox proportional hazard models. The associations were further delineated by Kaplan-Meier analysis using publicly available mRNA expression data. Our results show that nuclear HSF1 levels were elevated in ∼80% of in situ and invasive breast carcinomas. In invasive carcinomas, HSF1 expression was associated with high histologic grade, larger tumor size, and nodal involvement at diagnosis (P < 0.0001). By using multivariate analysis to account for the effects of covariates, high HSF1 levels were found to be independently associated with increased mortality (hazards ratio: 1.62; 95% confidence interval: 1.21-2.17; P < 0.0013). This association was seen in the estrogen receptor (ER)-positive population (hazards ratio: 2.10; 95% confidence interval: 1.45-3.03; P < 0.0001). In public expression profiling data, high HSF1 mRNA levels were also associated with an increase in ER-positive breast cancerspecific mortality. We conclude that increased HSF1 is associated with reduced breast cancer survival. The findings indicate that HSF1 should be evaluated prospectively as an independent prognostic indicator in ER-positive breast cancer. HSF1 may ultimately be a useful therapeutic target in cancer.heat-shock protein 90 | signature | pathology | heat-shock response | immunohistochemistry H eat-shock factor 1 (HSF1) is a multifaceted transcription factor that governs the cellular response to disruptions in protein homeostasis. To protect the proteome under various physiologic stresses, HSF1 drives the production of classic heatshock proteins (HSPs), such as HSP27, HSP70, and HSP90, that act as protein chaperones. This heat-shock response is an ancient adaptive mechanism that is present in eukaryotes from yeast to humans (1-3). The functions of HSF1 are not limited to increasing the expression of chaperones, however. HSF1 also modulates the expression of hundreds of genes other than chaperones that are critical for survival under an array of potentially lethal stressors (4, 5). As a result, HSF1 influences fundamental cellular processes such as cell-cycle control, protein translation, and glucose metabolism (5, 6).We have demonstrated that the multifaceted ability of HSF1 to promote survival in the face of lethal stressors is co-opted by cancer cells (6). In the malignant state, a litany of stressful conditions arises from the tumor microenvironment and from drastic internal changes in core cellular physiology that are hallmarks of cancer (7,8). HSF1 permit...

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Section: Discussionmentioning

confidence: 99%

High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

Santagata

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

274

273

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“…Re-routing of signal transduction pathways in response to therapy and selection of resistant subclones are two main components of acquired resistance [48][49][50]. At any given time, the degree of clonal diversity may be an indicator of risk for further disease progression depending upon the variation of subclones (Fig.…”

Section: Challenge: Drug Resistance and The Role Of Tumor Genetic DIVmentioning

confidence: 99%

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

Kemp

Shim

Heo

et al. 2016

Advanced Drug Delivery Reviews

416

258

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a b s t r a c t a r t i c l e i n f oThe dynamic and versatile nature of diseases such as cancer has been a pivotal challenge for developing efficient and safe therapies. Cancer treatments using a single therapeutic agent often result in limited clinical outcomes due to tumor heterogeneity and drug resistance. Combination therapies using multiple therapeutic modalities can synergistically elevate anti-cancer activity while lowering doses of each agent, hence, reducing side effects. Co-administration of multiple therapeutic agents requires a delivery platform that can normalize pharmacokinetics and pharmacodynamics of the agents, prolong circulation, selectively accumulate, specifically bind to the target, and enable controlled release in target site. Nanomaterials, such as polymeric nanoparticles, gold nanoparticles/cages/shells, and carbon nanomaterials, have the desired properties, and they can mediate therapeutic effects different from those generated by small molecule drugs (e.g., gene therapy, photothermal therapy, photodynamic therapy, and radiotherapy). This review aims to provide an overview of developing multi-modal therapies using nanomaterials ("combo" nanomedicine) along with the rationale, up-to-date progress, further considerations, and the crucial roles of interdisciplinary approaches.

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“…The difficult of analyzing tumor samples rises from the heterogeneity found in cancer cells that are subdue to different conditions depending on its location in the tumor (Michor et al, 2010). Besides, tumor samples are a mixture of these differents tumor cells and normal cells (Biankin & Hudson, 2011).…”

Section: Discussionmentioning

confidence: 99%