Tumors require a blood supply for growth and hematogenous dissemination. Much attention has been focused on the role of angiogenesis—the recruitment of new vessels into a tumor from pre-existing vessels. However, angiogenesis may not be the only mechanism by which tumors acquire a microcirculation. Highly aggressive and metastatic melanoma cells are capable of forming highly patterned vascular channels in vitro that are composed of a basement membrane that stains positive with the periodic acid-Schiff (PAS) reagent in the absence of endothelial cells and fibroblasts. These channels formed in vitro are identical morphologically to PAS-positive channels in histological preparations from highly aggressive primary uveal melanomas, in the vertical growth phase of cutaneous melanomas, and in metastatic uveal and cutaneous melanoma. The generation of microvascular channels by genetically deregulated, aggressive tumor cells was termed “vasculogenic mimicry” to emphasize their de novo generation without participation by endothelial cells and independent of angiogenesis. Techniques designed to identify the tumor microcirculation by the staining of endothelial cells may not be applicable to tumors that express vasculogenic mimicry. Although it is not known if therapeutic strategies targeting endothelial cells will be effective in tumors whose blood supply is formed by tumor cells in the absence of angiogenesis, the biomechanical and molecular events that regulate vasculogenic mimicry provide opportunities for the development of novel forms of tumor-targeted treatments. The unique patterning characteristic of vasculogenic mimicry provides an opportunity to design noninvasive imaging techniques to detect highly aggressive neoplasms and their metastases.

/pdf/vasculogenic-mimicry-and-tumor-angiogenesis-raik52nevn.pdf

Vasculogenic Mimicry and Tumor Angiogenesis

We performed a meta-analysis of all 87 published studies linking intratumoral microvessel density (MVD), reflecting angiogenesis, to relapse-free survival (RFS) and overall survival (OS). With median MVD as cutoff, MVD impact was measured by risk ratio (RR) between the two survival distributions. Seventeen studies did not mention survival data or fit inclusion criteria. Twenty-two were multiple publications of the same series, leaving 43 independent studies (8936 patients). MVD was assessed by immunohistochemistry, using antibodies against factor VIII (27 studies; n = 5262), CD31 (10 studies; n = 2296), or CD34 (8 studies; n = 1726). MVD might be a better prognostic factor when assessed by CD31 or CD34 versus factor VIII (P = 0.11). For RFS, statistical calculations were performed in 25 studies (6501 patients). High MVD significantly predicted poor survival [RR = 1.54 for RFS and OS with the same 95% confidence interval (CI), 1.29-1.84]. Twenty-two studies analyzed separately lymph node-negative patients (n = 3580), for whom predictors of poor survival are requested. This latter meta-analysis included 15 studies for RFS (2727 patients) and 11 for OS (1926 patients). High MVD significantly predicted poor survival [RR = 1.99 for RFS (95% CI, 1.33-2.98) and RR = 1.54 for OS (95% CI, 1.01-2.33)]. Between-study variations could result from patient selection criteria, techniques to stain and count microvessels, and cutoff selection. MVD was a significant although weak prognostic factor in women with breast cancer. Standardization of MVD assessment is needed.

https://cancerres.aacrjournals.org/content/canres/64/9/2941.full.pdf

Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis.

The discovery of new prognostic factors proceeds at a much more rapid pace than our knowledge of how to properly utilize this information in the management of patients with breast cancer, especially those with early breast cancer that has not metastasized to regional lymph nodes. Prognostic factors provide information on how the patient is likely to do regardless of treatment. Predictive factors provide information on whether a patient is likely to benefit from therapy. Most factors identified to date provide prognostic information, but relatively few provide information that is truly helpful in making a therapeutic decision in the management of individual patients. In large part this is because there has been insufficient study of the factor, especially prospective evaluations of the factor. Unfortunately this has resulted in the premature use of this information under the general rubric that patients with a poor prognosis deserve more treatment in spite of the fact that there may be no benefit from that therapy in the poor prognostic group.

The relationship between prognostic and predictive factors in the management of breast cancer

An interactive drug delivery system includes a drug delivery module, an optical probe, a local controller, and an optional central controller. The drug delivery module is constructed and arranged to deliver selected amounts of a drug into a subject. The optical probe is constructed and arranged to detect in a selected tissue region of the subject a manifestation caused by the delivered drug. The local controller is constructed and arranged to receive data from or transmit data to the optical probe and the drug delivery module. The local controller is arranged to correlate optical data, received from the optical probe, to selected data and provide signals to the drug delivery module for adjusting the amounts of the drug to be delivered into the subject.

Sensing and interactive drug delivery

Compelling experimental and clinical data support the concept that breast carcinoma, as most of the other solid tumors, needs to develop the angiogenic phenotype for invasiveness, progression and metastasis. Several studies have determined intratumoral microvessel density by panendothelial markers and immunohistochemical techniques, with most of them showing that the degree of vascularity is associated with prognosis of the patients operated of early-stage invasive breast cancer. More recently, certain angiogenic peptides have been assessed in human breast cancer: vascular endothelial growth factor (VEGF), platelet derived-endothelial cell growth factor (PD-ECGF, also known as thymidine phosphorylase, TP) and fibroblast growth factor family (FGFs). Among these, the most studied is VEGF, which appears to be a powerful prognostic indicator. Little data are available on the clinical significance of naturally occurring antiangiogenic factors, with few studies reporting on interleukin-12 and thrombospondins. In vivo techniques for dynamic assessment of tumor blood network are presently under extensive research, in particular for monitoring activity of inhibitors of angiogenesis. The methods of assessment of angiogenic activity and the results of published clinical studies in peer reviewed Journals with a computerized overview of literature will be presented. Overall, the results of the reported studies suggest that human breast cancer is an angiogenic-dependent tumor for which antiangiogenic therapy represents a promising novel antitumoral therapeutic strategy.

Clinical significance of determination of surrogate markers of angiogenesis in breast cancer

The importance of angiogenesis, assessed by tumour microvessel density, as a marker of survival was examined in 160 patients with infiltrating lobular carcinoma of the breast (ILC). The median follow-up was 5.1 years. Of these patients, 46 were node-negative, 59 were node-positive, and in 55 the pathological lymph node status was not known. Tumour sections were immunohistochemically stained with Factor VIII-related antibody. Microvessels were identified using previously recommended methodology and counted in three separate fields, selected from areas of highest vascularity, at x 200 magnification (field area = 0.785 mm 2 ). Only the highest count was considered in the analysis. No association was found between microvessel density and age, menopausal status, tumour size, histological subtype, peritumoural vessel invasion, and lymph node involvement at presentation. There was no association between microvessel density and overall survival or relapse-free survival. These results suggest that microvessel density assessment, using currently recommended methods, is unlikely to be of prognostic value in ILC.

Tumour angiogenesis as a prognostic marker in infiltrating lobular carcinoma of the breast.

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Tumour angiogenesis as a prognostic marker in infiltrating lobular carcinoma of the breast.