Posts Tagged ‘ctc’

Circulating tumor cell clusters more likely to cause metastasis than single cells

“While CTCs are considered to be precursors of metastasis, the significance of CTC clusters, which are readily detected using devices developed here at MGH, has remained elusive,” says Shyamala Maheswaran, PhD, of the MGH Cancer Center, co-senior author of the Cell paper. “Our findings that the presence of CTC clusters in the blood of cancer patients is associated with poor prognosis may identify a novel and potentially targetable step in the blood-borne spread of cancer.”

In their experiments the team used two versions of a microfluidic device called the CTC-Chip — both developed at the MGH Center for Engineering in Medicine — that captures CTCs from blood samples in ways that make the cells accessible for scientific testing. One version — the HBCTC-Chip — can efficiently capture extremely rare CTCs in a blood sample. Another version, the CTC-iChip, rapidly isolates CTCs in a way that does not rely on preidentified tumor antigens, allowing capture of cells with gene expression patterns that may be missed by the antibodies used in the HBCTC-Chip.

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

  • CTC clusters are made up of cells that probably were adjacent to each other in the primary tumor, not cells that proliferated after entering the bloodstream.
  • Although CTC clusters make up only 2 to 5 percent of all CTCs, they contributed to around half of lung metastases resulting from implanted breast tumors, indicating a metastatic potential 23 to 50 times greater than single CTCs.
  • CTC clusters injected into mice survived in greater numbers than did single CTCs, and metastases developing from clusters led to significantly reduced survival.
  • CTC clusters disappear from the animals’ bloodstreams more rapidly than do single CTCs, probably because they become lodged in capillaries where they give rise to metastases.

Analysis of blood samples taken at several points in time from a group of patients with different forms of advanced metastatic breast cancer found CTC clusters in the blood of 35 percent of patients and that the survival of those with more clusters in their blood was significantly reduced. Similar analysis of samples from a group of prostate cancer patients also found an association between the presence of CTC clusters and dramatically reduced survival.

RNA sequencing of both single and clustered CTCs from breast cancer patients identified several genes expressed at elevated levels in CTC clusters, one of which — a protein called plakoglobin — also was overexpressed in the primary tumors of patients with reduced survival. Analysis of blood and tissue samples from one patient revealed that plakoglobin was expressed in CTC clusters but not single CTCs and also was expressed in some portions of both the primary tumor and metastases. Plakoglobin is a component of two important structures involved in cell-to-cell adhesion, and the investigators found that suppressing its expression caused CTC clusters to fall apart, reducing their metastatic potential, and also disrupted cell-to-cell contact between breast cancer cells but not normal breast tissue.

“It is possible that therapeutically targeting plakoglobin or pathways involved in cell-to-cell adhesion within cancer cells could be clinically useful, especially in patients in whom CTC clusters are found,” says Nicola Aceto, PhD, of the MGH Cancer Center and lead author of the Cell paper. “We need to investigate that possibility along with determining whether further characterization of both single CTCs and CTC clusters will provide further insight into differences in their biology, drug responsiveness and their contribution to the process of metastasis.”

source : http://www.sciencedaily.com/releases/2014/08/140828135519.htm

Change in circulating tumor cells detection has potential in prediction of prostate cancer

"The research of the circulating tumour cells (CTC) is of utmost importance, because nowadays there is no reliable marker of both cancer-specific or overall survival in castration-resistant prostate cancer (CRPC) patients," explained the lead author of the study, Dr. Otakar Čapoun, of the Department of Urology at General Teaching Hospital Charles University in Prague, Czech Republic.

"The goal of this study is to assess the possibility of the individualisation of castration-resistant prostate cancer management. In cases with no favourable change in CTC detection during chemotherapy, the early switching to another therapy should be considered," commented Čapoun on the implications of the study, which was supported by the Internal Grant Agency of the Ministry of Health of the Czech Republic.

Protocol of the grant project included the collection of peripheral blood from patients with metastatic CRPC prior to docetaxel therapy and after the fourth cycle of chemotherapy (CTX). Circulating tumour cells were detected by using a method of immunomagnetic separation. In the course of the study multiplex-PCR was performed after cytolysis of CTC and the expression of tumour-associated antigens (PSA, PSMA and EGFR) was quantified.

The methodology of the study was based on verbal evaluation together with a report of the absolute values (ng/ml). The authors recorded the levels of serum PSA (sPSA) and the fragments of respective antigens before and in the course of CTX and compared the values. They also evaluated the correlation between the change of sPSA and expression of CTC antigens during CTX.

The study included 26 patients with both samples taken in 17 of them. Median age was 72 years (54-82), mean sPSA level before and after CTX was 197.6 and 120.1ng/ml, respectively. Before CTX only 2 out of 26 patients were considered CTC negative, whereas during the CTX the CTC negativity was confirmed in 9 out of 17 cases. Before CTX, positive detection of fragments of antigens for PSA, PSMA and EGFR was confirmed in 23, 16 and 2 patients, respectively, and during CTX in 8, 3 and 1 case, respectively. The sPSA level before CTX was associated with the level of fragments for PSA (p=0.0020) and PSMA (p=00.0147). During CTX the association was seen in all antigens. However neither a change in sPSA level nor a change in positive versus negative CTC statement correlated with a change of any of the tested antigens.

The study concludes that the sPSA level has the most accurate correlation with the level of gene fragment for PSA in CTC. A favourable change in CTC quantity will occur in more than a half of patients during chemotherapy, however the change in CTC detection does not correlate with the change of the sPSA level.

"This research project is divided into several arms, among others, we are investigating the feasibility of CTC cultivation and genetic profiling," commented Čapoun referring to the possibility of follow-up research.

"This gene profile will be compared with primary tumour at the time of diagnosis. In the future, this CTC profiling might be useful for even more accurate and better tailored selection of treatment for castration-resistant prostate cancer."

source : http://www.sciencedaily.com/releases/2013/10/131011135228.htm