Experimental evidence suggests that platelets contribute to metastasis through adhesive and haemostatic functions that promote cancer cell survival, immune evasion and interactions with vascular cells to assist organ colonization from the bloodstream. Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.

Contribution of platelets to tumour metastasis.

Blood platelets have long been recognised to bring about primary haemostasis with deficiencies in platelet production and function manifesting in bleeding while upregulated function favourises arterial thrombosis. Yet increasing evidence indicates that platelets fulfil a much wider role in health and disease. First, they store and release a wide range of biologically active substances including the panoply of growth factors, chemokines and cytokines released from a-granules. Membrane budding gives rise to microparticles (MPs), another active participant within the blood stream. Platelets are essential for the innate immune response and combat infection (viruses, bacteria, micro-organisms). They help maintain and modulate inflammation and are a major source of pro-inflammatory molecules (e.g. P-selectin, tissue factor, CD40L, metalloproteinases). As well as promoting coagulation, they are active in fibrinolysis; wound healing, angiogenesis and bone formation as well as in maternal tissue and foetal vascular remodelling. Activated platelets and MPs intervene in the propagation of major diseases. They are major players in atherosclerosis and related diseases, pathologies of the central nervous system (Alzheimers disease, multiple sclerosis), cancer and tumour growth. They participate in other tissue-related acquired pathologies such as skin diseases and allergy, rheumatoid arthritis, liver disease; while, paradoxically, autologous platelet-rich plasma and platelet releasate are being used as an aid to promote tissue repair and cellular growth. The above mentioned roles of platelets are now discussed.

Platelets, inflammation and tissue regeneration

The role of CXC chemokines and their receptors in cancer

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2010.04131.x

The platelet contribution to cancer progression.

Platelet-rich plasma has anti-inflammatory properties and is an important source of molecules that are involved in the repair and regeneration of tissues. PRP therapy, therefore, has great potential for aiding the healing response and repairing joint damage in patients with osteoarthritis. In this comprehensive Review, the authors describe the biological processes of PRP tissue engineering as well as the novel applications and approaches of PRP therapy in the context of targeting joint degeneration. Osteoarthritis (OA) is a common disease involving joint damage, an inadequate healing response and progressive deterioration of the joint architecture. Autologous blood-derived products, such as platelet-rich plasma (PRP), are key sources of molecules involved in tissue repair and regeneration. These products can deliver a collection of bioactive molecules that have important roles in fundamental processes, including inflammation, angiogenesis, cell migration and metabolism in pathological conditions, such as OA. PRP has anti-inflammatory properties through its effects on the canonical nuclear factor κB signalling pathway in multiple cell types including synoviocytes, macrophages and chondrocytes. PRP contains hundreds of different molecules; cells within the joint add to this milieu by secreting additional biologically active molecules in response to PRP. The net results of PRP therapy are varied and can include angiogenesis, the production of local conditions that favour anabolism in the articular cartilage, or the recruitment of repair cells. However, the molecules found in PRP that contribute to angiogenesis and the protection of joint integrity need further clarification. Understanding PRP in molecular terms could help us to exploit its therapeutic potential, and aid the development of novel treatments and tissue-engineering approaches, for the different stages of joint degeneration.

Platelet-rich plasma for managing pain and inflammation in osteoarthritis

Platelets sequester angiogenesis regulatory proteins early in tumor growth, which suggests a new avenue for monitoring disease. To date, there are no clinically relevant reference ranges for markers of early angiogenesis. We introduce a new ELISA-based method for accurate and reproducible measurement of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), platelet factor 4 (PF4), thrombospondin-1 (TSP-1), fibroblast growth factor, basic (bFGF), and endostatin in platelets. To facilitate clinical applicability, the platelet levels in isolated samples were determined utilizing a new actin ELISA method. Platelets from healthy donors at single and repetitive time points were used for the assessment of normal ranges of these proteins. The physiological levels in platelets were: VEGF (0.74 +/- 0.37 pg/10(6) platelets); PDGF (23 +/- 6 pg/10(6)); PF4 (12 +/- 5 ng/10(6)); TSP-1 (31 +/- 12 ng/10(6)); bFGF (0.44 +/- 0.15 pg/10(6)); and endostatin (5.6 +/- 3.0 pg/10(6)). There was an excellent correlation (R(2) = 0.7) between the platelet levels calculated with the actin ELISA and complete blood count. The levels of the platelets were higher than those in platelet-poor plasma by factors of: VEGF (215-fold); PDGF (914-fold); PF-4 (516-fold); TSP-1 (813-fold); and bFGF (17-fold). The endostatin levels were nearly equivalent. The biovariability of the platelet proteins in eight healthy subjects over a 5-week period was found to be minimal. We describe accurate and direct measurements of the concentrations of VEGF, bFGF, PDGF, TSP-1, endostatin, and PF4 in platelets of healthy human subjects. In contrast to the highly variable levels in plasma and serum, the platelet-derived measurements were accurate and reproducible with minimal biovariability.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.21732

Jon E. Peterson

Papers

Normal ranges of angiogenesis regulatory proteins in human platelets

Platelet-associated PF-4 as a biomarker of early tumor growth