CTC groups cause

CTC groups cause - metastases

circulating tumor cells (CTC) clusters - cluster of cells from 2 to 50 tumor that detach from a primary tumor and is transported by blood flow - appear to be much more likely to cause metastases that are simple CTCs, according to a study from researchers at Massachusetts General Hospital (MGH) Cancer Center. Their report in the August 28th issue cell also suggests that CTC clusters linking together of cell adhesion proteins is a potential therapeutic target.

"Although CTC are considered metastases precursors, the importance of clusters of the CTC, which are easily detected using devices developed here at MGH, has remained elusive," said Shyamala Maheswaran, PhD , of the MGH Cancer Center, co-lead author of the Cell paper. "Our findings that the presence of CTC clusters in the blood of cancer patients is associated with a poor prognosis may identify a novel and potentially targeted step in the spread by blood cancer."

In their experiments, the team used two versions of a microfluidic device called the CTC-Chip - both developed at MGH medical engineering center - which capture CTCs from blood samples so as to make the cells accessible to the scientific tests. One version - the ^HB CTC-Chip - can effectively capture extremely rare CTCs in a blood sample. Another version, the CLC-iChip quickly isolated CTCs in a manner that does not rely on pre-identified tumor antigens, allowing the capture cells with the gene expression profiles that may be missed by the antibodies used in the ^HB CTC. chip

A series of experiments on animal models of breast cancer revealed that:

• CTC clusters are made up of cells that were probably adjacent to each other in the primary tumor, not the cells that proliferated after entering the bloodstream.

• Although CTC clusters represent only 2 to 5 percent of all CTC, they contributed to nearly half of lung metastases resulting from implanted breast tumors, indicating metastatic potential 23-50 times higher than single CTCs.

• CTC clusters injected into mice survived in greater numbers than single CTCs, and clusters of developing metastases led to a significant reduction in survival.

• CTC clusters disappear animal blood faster than single CTCs, probably because they become lodged in the capillaries where they give rise to metastases.

Blood sample analysis taken at several time points from a group of patients with various forms of advanced metastatic breast cancer found clusters of CTCs in the blood 35 percent of patients and the survival of people with several clusters in the blood was significantly reduced. A similar analysis of samples from a group of prostate cancer patients also found an association between the presence of clusters of CTC and survival greatly reduced.

RNA sequencing of two single CTCs and group of patients with breast cancer identified several genes expressed high levels of CTC clusters which - a protein called plakoglobin - also overexpressed in primary tumors of patients with reduced survival. Analysis of samples of blood and tissues of a patient revealed that plakoglobin was expressed in clusters of CTC CTC but not as simple and was expressed in parts of both the primary tumor and metastasis. Plakoglobin is a component of two important structures involved in cell-cell adhesion, and the researchers found that the suppression of expression caused CTC clusters to disintegrate, reducing their metastatic potential, and also disrupted Contact cell to cell between the breast cancer cells but not normal breast tissue.

"It is possible that therapeutic targeting plakoglobin or pathways involved in cell-cell adhesion in cancer cells could be clinically useful, particularly in patients who are clusters CTC" says Nicola Aceto, PhD, of the MGH Cancer Center and senior author of the paper Cell. "We need to study this possibility and determine if further characterization of the two groups and the CTC CTC only provide further information differences in their biology, the reactivity of drugs and their contribution to the process of metastasis. "