Tumor heterogeneity and circulating tumor cells

Zhang, Chufeng; Guan, Yan; Sun, Yulan; Ai, Dan; Guo, Qisen

doi:10.1016/j.canlet.2016.02.024

Cited by 70 publications

(63 citation statements)

References 119 publications

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“…While these kinds of assays still need further validation before they can be adopted into clinical practice, blood-based assays are extremely appealing to clinicians and researchers. Importantly these assays are known to detect evidence of the common tumor heterogeneity, which needs to be accounted for in biomarker analysis [8]. …”

Section: Introductionmentioning

confidence: 99%

Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies

Luk

Young

et al. 2016

IJMS

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Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs) or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies.

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Section: Introductionmentioning

confidence: 99%

Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies

Luk

Young

et al. 2016

IJMS

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“…The process of epithelial-to-mesenchymal transition (EMT) leads to the loss of epithelial markers such as E-cadherin and EpCAM, over expression of N-cadherin, and cytoskeletal alterations (e.g., expression of vimentin), finally producing phenotypical and structural changes that lead to an increased motility and invasiveness [38,57,74,75]. Importantly, intermediate phenotypes between epithelial and mesenchymal differentiation can exist.…”

Section: Ctc Intrinsic Heterogeneitymentioning

confidence: 99%

“…These two ways of computing OS are conceptually related to two different models of cancer pathophysiology. The first one hypothesizes that cancer is characterized by a spatial- and temporal-heterogeneity and CTC analyses can be employed to monitor, in real time, the metastatic dissemination [38]. On the contrary, according to the second one, the detection of EM-CTC seems to predict a metastatic disease that is intrinsically drug-resistant.…”

Section: Ctc Intrinsic Heterogeneitymentioning

confidence: 99%

“…Besides looking for known mutations, as described above, the development of whole genome amplification (WGA) followed by high-throughput sequencing (also called “next-generation sequencing”, NGS), microarray-based comparative genomic hybridization (array-CGH), and single-cell sequencing (SCS) techniques make it possible to profile single CTC [38,110]. Once optimized the best strategies to isolate single and pure CTC suitable for downstream analyses [48,111], this would allow to address important issues including: the ability of CTC to capture the genetic heterogeneity of primary and metastatic tumors (and therefore of all the possible drug targets); the variability of CTC isolated from the same patients; and the possibility, through CTC analyses, to monitor in real-time the appearance of resistant clones, possibly bearing druggable variants.…”

Section: Ctc Intrinsic Heterogeneitymentioning

confidence: 99%

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Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack

Bulfoni

Turetta

Ben

et al. 2016

IJMS

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Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM+/CK+) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a “surrogate” of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug-resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well.

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“…Pathogenic variants occurring after treatment are not detected without another biopsy, sometimes long after the tumor has acquired resistance to that treatment. Metastasized tumors are particularly difficult to assess with tissue biopsies, because usually only one tumor is biopsied and analyzed, leaving tumors in other sites uncharacterized, thus missing the complete genomic cancer profile [13] . Consequently, multiregional and repeated tumor biopsies to assess tumor heterogeneity are not always practical or feasible due to the associated risks and complications as well as patient comorbidity, costs, spatial heterogeneity within the tumor, lack of safe access to the lesion, and sampling bias [14,15] .…”

Section: Introductionmentioning

confidence: 99%

Exosomes: A Cancer Theranostics Road Map

Panagiotara

Markou

Lianidou

et al. 2017

Public Health Genomics

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Interindividual variability is yet to be fully characterized, and for this, optimum patient stratification and companion diagnostics are still lacking. Especially when complex disease phenotypes and/or polygenic diseases are considered, patient monitoring and disease management become rather challenging, while acquired resistance to therapy and/or toxicity events are among the unmet needs in the clinic. No doubt, biomarkers are of great importance to disease management and tailor-made theranostics. Microfluidics has gathered great attention lately, mostly due to its low-invasive nature compared to tissue biopsies. Low invasiveness becomes greatly advantageous for microfluidics practices as the latter mirror cell biology revolutionizing cancer diagnostics and management. Recent advances in microfluidics hold the promise of robust clinical diagnostics after they have demonstrated effective exosome separation. We feel that microfluidics-based exosome isolation techniques, if cost-effective, could be implemented in the clinic and/or resource-scarce settings. This article (a) discusses exosomes, (b) comments on the first microfluidic advances in the field of cancer theranostics, (c) presents such advances in exosomes as complementary to liquid biopsies with an emphasis on circulating tumor cells, and (d) proposes a road map for future developments.

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Tumor heterogeneity and circulating tumor cells

Cited by 70 publications

References 119 publications

Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies

Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies

Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack

Exosomes: A Cancer Theranostics Road Map

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