Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize

Giuliano, Mario; Shaikh, Anum; Lo, Hin Ching; Arpino, Grazia; Placido, Sabino De; Zhang, Xiang H.-F.; Cristofanilli, Massimo; Schiff, Rachel; Trivedi, Meghana V.

doi:10.1158/0008-5472.can-17-2748

Cited by 175 publications

(171 citation statements)

References 58 publications

(64 reference statements)

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“…48 Targeted removal of HA and HS increased permeability of the MVNs to 70 kDa dextran by 1.4-and 49 1.7-fold compared to untreated control networks, respectively ( Fig. 1b), consistent with the idea 50 that the EC GCX can sterically hinder passage of macromolecules 32 . Indeed, this increase in 51 permeability was not likely due to disrupted endothelial cell-cell junctions since ZO-1 localization 52 revealed no visible changes in tight junction morphology, and treatment with the pro-inflammatory 53 factor TNF-α, known to disrupt both the EC GCX and EC junctions 33,34 , produced a much larger 6.9- 54 fold increase in permeability (not shown).…”

Section: Introductionsupporting

confidence: 79%

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Offeddu

Hajal

Foley

et al. 2020

Preprint

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The glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using an in vitro model of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a novel mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Transendothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.

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Section: Introductionsupporting

confidence: 79%

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Offeddu

Hajal

Foley

et al. 2020

Preprint

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“…In addition to single CTCs, CTC clusters (CTCCs; also called circulating tumor microemboli; CTM) are multicellular groupings of CTCs that exhibit a mixture of epithelial and mesenchymal properties, and may include stromal (14) and other non-tumor cells (15,16).…”

Section: Introductionmentioning

confidence: 99%

In VivoMonitoring of Rare Circulating Tumor Cell and Cluster Dissemination in a Multiple Myeloma Xenograft Model

Patil

Tan

Bartosik

et al. 2019

Preprint

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We recently developed 'Diffuse in vivo Flow Cytometry' (DiFC), a new pre-clinical research tool for enumerating extremely rare fluorescently-labeled circulating cells directly in vivo. In this paper, we developed a green fluorescent protein (GFP) compatible version of DiFC, and used it to non-invasively monitor the circulating tumor cell (CTC) burden over time in a multiple myeloma disseminated xenograft model. We show that DiFC allowed counting of CTCs at estimated concentrations below 1 cell per mL in peripheral blood with a negligible false alarm rate. DiFC also revealed the presence of CTC clusters in circulation to our knowledge for the first time in this model, and allowed us to calculate their size, kinetics, and frequency of shedding. We anticipate that the unique capabilities of DiFC will have many applications in the study of hematogenous metastasis, and as a powerful complementary methodology to liquid biopsy assays.

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“…CTC could be a single or cluster of cells that initiate metastasis. A clustered CTC is more metastatic than a single CTC (20–22). It is evident that the mutant p53 phenotype is selected mostly by CP which might explain the enhanced metastatic tendency of clustered CTC (23).…”

Section: Discussionmentioning

confidence: 99%

Oxygen-generated spatial distribution of cell population links to p53 status

Taxak

Pati

2019

Preprint

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17Low oxygen induces wild type p53 inactivation and selects for mutant-like p53 18 phenotypes for aggressive tumor growth. Recently, we have shown wild type p53 as 19 a cellular oxygen-sensor that operates in switch-like fashion to transform its 20 characters of a tumor suppressor or promoter in a gradient of hypoxia. However, it is 21 unclear how hypoxic tumors select for wild type p53 phenotypes for oxygen-22 sensitive responses. Here, we show that oxygen-generated spatial distribution of the 23 cell population induces p53 phenotype-specific survival or death. We have found 24 that a dynamic state of spatial scatters or clustering patterns of cell populations 25 favor the survival of wild type more than the mutant phenotypes in a wide range of 26 oxygen fluctuation by affecting p53 subcellular localization. Our results demonstrate 27 how spatial distribution could function to establish wild type p53-mediated oxygen 28 sensing and cell fate decisions in a cell population with heterogeneous p53 allele 29 status. We anticipate that such behavior of cells in a gradient of oxygen can be 30 utilized by the hypoxic tumors to maintain distinct p53 alleles and determine the 31 release and metastasis of single or clustered circulating tumor cells (CTCs).32 33 129 Pune), and DU145 p53 WT/MT (NCCS, Pune) were cultured in Dulbecco's modified Eagle's medium 130 (Merck, D5648) supplemented with 10% (v/v) FCS (Thermofisher, 10438018), penicillin (100 131 U/ml), streptomycin (100 U/ ml) and L-glutamine (4 mM) (Merck, G3126), pH 7.4. For the 132 proliferating cell cultures, 5% CO 2 was maintained in a humidified incubator at 37 °C. Hypoxia 133 exposure to the cell culture was performed under a humidified condition in a hypoxia chamber 134 (Plas Labs inc., USA) equipped with O 2 and CO 2 sensors. O 2 and CO 2 levels were quickly restored 135 upon the detection of fluctuations (by ±0.2 units) from the set levels through the automated 136 purging of gases by inbuilt sensors. The normal atmospheric pressure was maintained through 137 the N 2 gas. Similarly, the integrated thermostat maintained the temperature at 37°C. Just before 138 the exposure, DMEM was replenished in the cultures. Re-oxygenation was performed by 139 transferring the cultures from the hypoxia chamber to the CO 2 (5%) incubator for a 24h period.140 Flow cytometry 141 Following the treatments, cells were rinsed with PBS and harvested by mild trypsinization 142 for 10-15 seconds at 37°C. The trypsinized cells were gently detached with chilled PBS 143 supplemented with 2% FBS. The cells were gently washed and diluted (approx. 30,000 cells per 144 173 were washed and blocked in 4% BSA in PBS (with 0.1% TX-100) overnight at 4°C. 174 Endogenous p53 was detected by anti-p53DO1 primary antibody (1:1000 dilutions) at 22°C 175 for 4h. Indirect immune labeling was performed by FITC-tagged secondary antibody (1:5000 176 dilutions) for 2h in dark at room temperature. From now onwards all procedures were 177 performed in dark. Secondary antibodies were washed and SlowFade antif...

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Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize

Cited by 175 publications

References 58 publications

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

In VivoMonitoring of Rare Circulating Tumor Cell and Cluster Dissemination in a Multiple Myeloma Xenograft Model

Oxygen-generated spatial distribution of cell population links to p53 status

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