Improving Understanding Of Cell Behaviour In Breast Cancer
Main Category: Breast CancerAlso Included In: Lymphology/Lymphedema
Article Date: 19 Jun 2008 - 5:00 PDT
The invasion and spread of cancer cells to other parts of the body, known as metastasis, is a principal cause of death in patients diagnosed with breast cancer. Although patients with early stage, small, breast tumours have an excellent short term prognosis, more than 15 to 20 per cent of them will eventually develop distant metastases, and die from the disease. Vascular invasion through lymphatic and blood vessels is the major route for cancer spreading to regional lymph nodes and to the rest of the body.
Dr Stewart Martin, Professor Ian Ellis and their colleagues at The University of Nottingham, and worldwide, are combining a number of approaches in a dynamic effort to improve our understanding of cell behaviour in breast cancer. Discovering how these cells operate is vital in improving diagnosis and treatment for the cancer patient in the longer term, and in identifying therapeutic targets. Already the results of their work have been excellent with findings in relation to the spread of cancer through the lymphatic vessels prompting a much larger study funded by Cancer Research UK.
A research student within the Nottingham team, Rabab Mohammed, showed recently that specific factors that regulate the growth of blood and lymphatic vessels can identify a subset of tumours which have a high probability of recurring or spreading.
The team subsequently identified the crucial importance of assessing both the level of blood and lymph vessel invasion by cancer cells at the earliest stages of detection. It has, until recently, been very difficult to distinguish between the two. With advances in immunohistochemical techniques, blood vessels can today be reliably identified and differentiated from lymphatics. Currently clinical approaches for the assessment of vascular invasion are insufficiently robust and can result in a failure to detect some lesions accurately, or fail to differentiate adequately between blood and lymph vessels. The Nottingham team has shown using tumour sections from 177 patients that 96 per cent of vascular invasion in primary invasive breast cancer is predominantly of the lymph vessels. This is significant.
It is important that this finding is verified in a larger cohort of patients. The researchers are now working to accomplish this, through funding recently obtained from Cancer Research UK, using specimens from more than a thousand women with early stage breast cancer. Results from this study will also allow them to determine whether Lymphatic Vascular Invasion can be incorporated into an improved prognostic index for early stage breast cancer.
This work is being combined with gene expression studies, with bioinformatic approaches and using in vitro (cells in culture) models to identify novel therapeutic targets. It is being conducted in collaboration with a number of groups, industrial and academic, from both the UK and overseas.
NOTTINGHAM UNIVERSITY
University Park
Nottingham
NG7 2RD
http://www.nottingham.ac.uk
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Cancer And Angiogenesis
posted by Gregory D. Pawelski on 19 Jun 2008 at 10:24 pmIn normal tissue, new blood vessels are formed during tissue growth and repair, and the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.
Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.
Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.
About 15 proteins are known to activate endothelial cell growth and movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (acidic and basic), interleukin 8, prostaglandin E1 and E2, tumor necrosis factor-, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 ( and ß), interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinase-1 and -2. (TIMP-1 and -2).
At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.
Since angiogenesis is also related to metastasis, it is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion.
A microvascular viability biomarker was developed based upon the principle that microvascular cells are present in tumor cell microclusters obtained from solid tumor specimens. A major modificaton of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents, such as Avastin, Nexavar, and Sutent. The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect (clinical responders).
Source: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007
History Of The ER Assay
posted by Gregory D. Pawelski on 5 Aug 2008 at 8:49 amThe ER assay is used to determine a number of very important things. Which patients with early breast cancer should receive adjuvant chemotherapy. Whether or not chemotherapy should include hormonal therapy. In the advanced setting, whether chemotherapy should be given versus hormonal therapy. These are all very important decisions. The stakes are high with the ER assay, in terms of potentially harming the patient.
The ER assay was developed in the mid 1970s. First generation technology was a complicated lab test called the radioligand binding assay (RLB assay). The accuracy of this assay was mainly documented by retrospective correlations, in hundreds and not thousands of patients. Patients who were ER negative were said to have about 10% chance of responding to hormonal therapy and were more likely to recur after "curative" surgery. Patients who were ER positive had about a 60% chance of responding and were less likely to recur. No one ever did a prospective randomized trial to prove that doing the assay made a difference; there were just retrospective studies correlating assay results with clinical response to treatment.
In the early 1980s, the technology was changed from the complicated RLB assay, which could be done only in a few highly specialized laboratories to a much more simple immunohistochemical (microscope slide) assay, which could be done in most pathology labs. This newer assay was initially validated by comparison of the RLB assay in the specialized labs. The new assay correlated reasonably well with the older assay and it replaced the older assay. No one ever did a prospective or even retrospective study to show how the newer assay correlated with and predicted for response to treatment. It was just "the old assay works and the new assay correlates (in a few, highly specialized laboratories) with the old assay; so the new assay is OK to use."
In 2006, there was finally a study (in a highly sophisticated laboratory) showing how well the new assay predicts. In a very small study, which was retrospective, meaning they could draw the best possible cut off lines after the fact, they found that ER positive patients had a 56% response rate, while ER negative patients had a 20% response rate. Correlations which are vastly inferior to those obtained in much bigger and better studies with cell culture assays.
If a highly sophisticated lab gets such lousy correlations, then you can imagine the accuracy of tests done in community hospitals. And yet every patient with breast cancer gets this test and in almost every patient the information is used to make much more critical decisions than in the cases of both the Her2/neu assay and also the cell culture assay.
Questions regarding the best methodology of HER2 testing as well as the clinical applications of such testing remain. Ultimately, the most useful test will be the one that correlates best with HER2-mediated cellular biology and clinical outcome. The comparison of HER2 detection with clinical end points will allow clarification of the predictive value of a particular method.
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