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circulating tumor cells

Wednesday 31 May 2006

circulating tumoral cells, CTCs, circulating cancer cells

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Malignant cells circulate in the bloodstream of patients with solid tumors.

Metastasis

Tumor metastasis is one of the hallmarks of malignant cancer and is considered to be
the cause of 90% of cancer-related human deaths. The major threat of cancer disease is therefore the spread of malignant cells from a primary tumor and formation of metastatic secondary tumors in host organs. Cancer metastasis is a complex multi-step process influenced by numerous
cellular and molecular characteristics of both host organ and tumor. During hematogenous metastasis, epithelial cancer cells detach from the primary tumor, migrate, and intravasate into the vascular system through capillary vessels.

Cancer cells from a primary tumor transported in the blood stream are called circulating tumor cells (CTCs). CTCs spread with circulation to remote sites; and subsequently, they can extravasate from the vascular system through blood vessel walls into the surrounding tissue forming secondary tumors at host organs.

CTC extravasation

CTC extravasation is one of the most crucial stages in cancer-disease development leading to the establishment of secondary micrometastases in host organs. While the extravasation of white blood cells in the presence of inflammation/infection at an injury site is well documented, extravasation of CTCs is still unknown.

The “seed-and-soil” hypothesis stipulates that cancer cells spread randomly to other organs, but survive only in sites that produce appropriate growth factors.

In contrast, the “homing” hypothesis of organ-selective cancer metastasis, due to
specific protein-protein interactions, is currently gaining popularity. In this regard, several studies proposed the involvement of receptors and localized chemokine signals in directing tumor cells to certain organs and site of the body.

Extravasation of circulating cells consists of:
- (i) initial adherence by binding to endothelial cells resulting in a rolling motion,
- (ii) firm adhesion leading to a complete arrest adjacent to a vessel wall,
- (iii) transmigration across the endothelium, squeezing between adjacent endothelial cells, into the surrounding tissue.

Two mechanisms have been proposed for CTC arrest on a vessel wall:
- (i) specific biochemical interaction between CTCs and activated endothelial cells similar to initial inflammatory response
- (ii) entrapment of CTCs in small vessels due to size restriction as they tend be relatively large.

Both arrest mechanisms have been observed, and it is still not clear which mechanism is dominant or whether different CTCs are prone to a particular mechanism.

Furthermore, following transmigration, tumor-cell invasiveness and secondary-tumor formation depend on the interaction of the invading tumor cells with both host cells and extracellular matrix (ECM) components in a complex microenvironment. The effects of microenvironmental conditions and guiding signals within the surrounding tissue on CTC extravasation have yet to be well understood.

CTCs in circulation

Once in the bloodstream, CTCs face several natural obstacles that hinder the metastatic process.

First are the enormous shearing forces and collisions with blood cells, generated by blood flow. Although shear stresses decrease the number of viable cancer cells dramatically, tumor cells that underwent EMT seem to be more resistant against these forces compared to epithelial tumor cells (Mitchell & King, 2013).

Second, CTCs must survive in the bloodstream without their cell–matrix interactions, an occurrence that would normally trigger apoptosis through a process called anoikis. Resistance against anoikis, however, is made possible in CTCs by activated tropomyosin-related kinase B (TrkB) that suppresses caspase-associated apoptosis and enables the cells to survive in liquid suspension (Douma et al, 2004).

The third obstacle that CTCs face in the blood is the activity of the immune system. In colorectal cancer, immune escape is obtained by up-regulation of CD47 that prevents CTCs from macrophage and dendritic cell attack (Steinert et al, 2014).

Finally, cancer cells must eventually leave the blood circulation, which requires binding to the endothelium lining the vessels. Because platelets enhance this binding, inhibition of platelet aggregation by for instance aspirin can decrease stable tumor cell binding to activated platelets (Uppal et al, 2014).

Prognosis

Current efforts in several tumor types have shown that patients in whom circulating tumor cells (CTCs) are detected have an inferior prognosis relative to those in whom CTCs are not detected and that the elimination or decrease of CTCs following treatment is associated with improved clinical outcomes.

Biomarkers in CTCSs

- biomarkers in circulating tumor cell

  • DNA biomarkers in circulating tumor cells
  • RNA biomarkers in circulating tumor cells
  • miRNA biomarkers in circulating tumor cells
  • protein biomarkers in circulating tumor cells

Reviews

- Alix-Panabieres C, Pantel K. Technologies for detection of circulating tumor cells: facts and vision. Lab Chip. 2014;14:57–62. [http://www.ncbi.nlm.nih.gov/pubmed/24145967]

- Alix-Panabieres C, Pantel K. Circulating tumor cells: liquid biopsy of cancer. Clin Chem. 2013;59:110–118. [http://www.ncbi.nlm.nih.gov/pubmed/23014601]

- Alix-Panabieres C, Schwarzenbach H, Pantel K. Circulating tumor cells and circulating tumor DNA. Annu Rev Med. 2012;63:199–215. http://www.ncbi.nlm.nih.gov/pubmed/22053740

- Punnoose EA, et al. Molecular biomarker analyses using circulating tumor cells. PLoS One. 2010;5(9):e12517. PMID: 20838621

- Circulating tumor cells as emerging tumor biomarkers in breast cancer. Lianidou ES, Markou A. Clin Chem Lab Med. 2011 Oct;49(10):1579-90. PMID: 21801030 [Free]

- Mocellin S, Keilholz U, Rossi CR, Nitti D. Circulating tumor cells: the ’leukemic phase’ of solid cancers. Trends Mol Med. 2006 Mar;12(3):130-9. PMID: 16488189

Open References

- Circulating Tumor Cells Count and Morphological Features in Breast, Colorectal and Prostate Cancer. Ligthart ST, Coumans FA, Bidard FC, Simkens LH, Punt CJ, de Groot MR, Attard G, de Bono JS, Pierga JY, Terstappen LW. PLoS One. 2013 Jun 27;8(6):e67148 . PMID: 23826219 [Free]

- Detecting circulating tumor cells: current challenges and new trends. Hong B, Zu Y. Theranostics. 2013 Apr 23;3(6):377-94. doi : 10.7150/thno.5195 PMID: 23781285 [Free]

- Clinical challenges in the molecular characterization of circulating tumour cells in breast cancer. Lianidou ES, Mavroudis D, Georgoulias V. Br J Cancer. 2013 Jun 25;108(12):2426-32. doi : 10.1038/bjc.2013.265 PMID: 23756869

- Circulating tumor cells: liquid biopsy of cancer. Alix-Panabières C, Pantel K. Clin Chem. 2013 Jan;59(1):110-8. doi : 10.1373/clinchem.2012.194258 PMID: 23014601

- Gene expression profile of circulating tumor cells in breast cancer by RT-qPCR. Strati A, Markou A, Parisi C, Politaki E, Mavroudis D, Georgoulias V, Lianidou E. BMC Cancer. 2011 Oct 4;11:422. PMID: 21967632 [Free]

- Assessment of a six gene panel for the molecular detection of circulating tumor cells in the blood of female cancer patients. Obermayr E, Sanchez-Cabo F, Tea MK, Singer CF, Krainer M, Fischer MB, Sehouli J, Reinthaller A, Horvat R, Heinze G, Tong D, Zeillinger R. BMC Cancer. 2010 Dec 3;10:666. PMID: 21129172 [Free]

References

2013

- Essentials of circulating tumor cells for clinical research and practice. Liberko M, Kolostova K, Bobek V. Crit Rev Oncol Hematol. 2013 Jul 4. doi : pii: S1040-8428(13)00096-6.10.1016/j.critrevonc.2013.05.002 PMID: 23830807

- Prostate Cancer: A Change in Circulating Tumor Cells Detection Has High Potential in the Prediction. October 11, 2013. By European Association of Urology http://www.sciencenewsline.com/articles/2013101116100003.html

- Circulating tumor cells and DNA as liquid biopsies. Heitzer E, Auer M, Ulz P, Geigl JB, Speicher MR. Genome Med. 2013 Aug 23;5(8):73. PMID: 23998943

- Clinical significance of circulating tumor cells in peripheral blood from patients with gastric cancer. Uenosono Y, Arigami T, Kozono T, Yanagita S, Hagihara T, Haraguchi N, Matsushita D, Hirata M, Arima H, Funasako Y, Kijima Y, Nakajo A, Okumura H, Ishigami S, Hokita S, Ueno S, Natsugoe S. Cancer. 2013 Aug 20. doi : 10.1002/cncr.28309 PMID: 23963829

2011

- Circulating tumors cells as biomarkers: progress toward biomarker qualification. Danila DC, Pantel K, Fleisher M, Scher HI. Cancer J. 2011 Nov-Dec;17(6):438-50. doi : 10.1097/PPO.0b013e31823e69ac. Review PMID: 22157288

- Circulating tumors cells as biomarkers: progress toward biomarker qualification. Danila DC, Pantel K, Fleisher M, Scher HI. Cancer J. 2011 Nov-Dec;17(6):438-50. PMID: 22157288

- Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients
Diego M Marzese et al. Expert Review of Molecular Diagnostics, November 2013, Vol. 13, No. 8, Pages 827-844, doi : 10.1586/14737159.2013 845088

- Circulating cell-free DNA, SLC5A8 and SLC26A4 hypermethylation, BRAF V600E : A non-invasive tool panel for early detection of thyroid cancer. Zane M, Agostini M, Enzo MV, Casal Ide E, Del Bianco P, Torresan F, Merante Boschin I, Pennelli G, Saccani A, Rubello D, Nitti D, Pelizzo MR. Biomed Pharmacother. 2013 Jul 5. doi : pii:S0753-3322(13)00083-8 10.1016/j.biopha.2013.06.007. PMID: 23931930

- Clinical challenges in the molecular characterization of circulating tumour cells in breast cancer. Lianidou ES, Mavroudis D, Georgoulias V. Br J Cancer. 2013 Jun 25;108(12):2426-32. doi : 10.1038/bjc.2013.265 Epub 2013 Jun 11. Review. PMID: 23756869

- Plasma is a better source of tumor-derived circulating cell-free DNA than serum for the detection of EGFR alterations in lung tumor patients. Vallée A, Marcq M, Bizieux A, Kouri CE, Lacroix H, Bennouna J, Douillard JY, Denis MG. Lung Cancer. 2013 Aug 19. doi : pii:S0169-5002(13)00377-2.10.1016/j.lungcan.2013.08.014 PMID: 24007628