The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Neovasculature development is a crucial step in the natural history of a cancer. While much emphasis has been placed on proangiogenic growth factors such as VEGF, it is clear that endogenous angiogenesis inhibitors also have critical roles in the regulation of this process. Recent research has identified several cryptic fragments of extracellular matrix/vascular basement membrane proteins that have potent antiangiogenic properties in vivo. It has become apparent that many of these fragments signal via interactions with endothelial integrins, although multiple downstream effector pathways have been implicated and endostatin, the first non-collagenous domain of collagen XVIII, influences an intricate signalling network. The activity of these molecules in animal models suggests that they may have significant clinical activity; however, results of phase I/II trials with endostatin were disappointing. Many possible reasons can be found for the failure of these studies. Weaknesses in trial design, endostatin administration regimen and patient selection are identifiable, and importantly the lack of a clearly defined antiangiogenic mechanism for endostatin hindered assessment of biologically effective dose. Additionally, in vivo immunological and proteolytic function-neutralising mechanisms may have negated endostatin's actions. Lessons learned from these studies will aid the future clinical development of other antiangiogenic extracellular matrix protein fragments

PPARα Deficiency in Inflammatory Cells Suppresses Tumor Growth

Inflammation in the tumor bed can either promote or inhibit tumor growth. Peroxisome proliferator-activated receptor (PPAR)α is a central transcriptional suppressor of inflammation, and may therefore modulate tumor growth. Here we show that PPARα deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of the endogenous angiogenesis inhibitor thrombospondin-1 and prevents tumor growth. Bone marrow transplantation and granulocyte depletion show that PPARα expressing granulocytes are necessary for tumor growth. Neutralization of thrombospondin-1 restores tumor growth in PPARα-deficient mice. These findings suggest that the absence of PPARα activity renders inflammatory infiltrates tumor suppressive and, thus, may provide a target for inhibiting tumor growth by modulating stromal processes, such as angiogenesis

A review of clinical and molecular prognostic factors in osteosarcoma

Traditional prognostic determinants in osteosarcoma have included demographics (age, sex), tumour size, site, stage, and the response to chemotherapy. Many of these are determined using varying techniques and units of measurement, which can make comparison between studies diYcult. The absence of survival diVerence between limb sparing surgery and amputation has been repeatedly demonstrated in primary disease, and even in the setting of pathological fracture. On the other hand, there is still some controversy over the existence of increased local recurrence for limb-sparing surgery, and the implications of this. Commonly used prognostic determinants such as metastases, and response to chemotherapy enable a high degree of prognostic accuracy but usually at a late stage in the course of disease. Leading on from this, there is a need to uncover molecular pathways with speciWc inXuence over osteosarcoma progression to facilitate earlier treatment changes. Some important pathways are already being deWned, for example the association of CXCR4 with metastases on presentation, the likelihood of doxorubicin resistance with positive P-glycoprotein, and the reduced survival prediction of over expressed survivin. It is anticipated that the future of osteosarcoma treatment will involve treatment tailored to the molecular proWle of tumours at diagnosis, adjuvant therapy directed towards dysfunctional molecular pathways rather than the use of cytotoxics, and a more standardised approach to the measurement of clinical prognostic factors