Ajaz, Arzoo

Ali, Akbar Shoukat

Hamid, Heeba

English

eCommons@AKU

eCommons@AKUDepartment of Anaesthesia Medical College, PakistanMarch 2017Emerging protagonists in cancer metastasis: Anoath of allegiance by plateletsAkbar Shoukat AliAga Khan University, akbar.shoukatali@aku.eduArzoo AjazJinnah University of Women, Karachi, PakistanHeeba HamidJinnah University of Women, Karachi, PakistanFollow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_anaesthPart of the Anesthesia and Analgesia Commons, and the Anesthesiology CommonsRecommended CitationAli, A. S., Ajaz, A., Hamid, H. (2017). Emerging protagonists in cancer metastasis: An oath of allegiance by platelets. JPMA. TheJournal of the Pakistan Medical Association, 67(3), 330-332.Available at: https://ecommons.aku.edu/pakistan_fhs_mc_anaesth/230The global burden of cancer is burgeoning at steady rate onaccount of genetic insults (5-10%), as well as an increasingprevalence of unhealthy andpreventable lifestyle risk factors(90-95%) such as smoking, alcohol, stress and sedentaryhabits.1More recentmortality data suggests that, in 2012, 8.2million cancer deaths were registered globally.2 Annualdeath toll, besides, is estimated to heighten, by 2030, to 13.1million.3 Mortality trend attributes 90% of cancer-associateddeaths to metastasis, a perturbing phenomenon inoncological medicine that endows cancer with thepropensity to dodge immunological hijacking, pervade andsurvive circulatory territory, and reproduce within distinctcellular lineages (distant organ systems) through complexcellular and molecular signals.4 Indeed, metastasis-assistedmortalitieshave reachedpandemicproportions. Regrettably,the underlying molecular pathways harmonizing thedissemination of primary tumour to remote tissues of thebody remain to be uncovered.Metastasis represents the sequential and successfultransfiguration of tumour cells to encroach establishednearby (primary) and distant (secondary) tissues integrity,stochastically by compromising their genetically scriptedcellular behaviour. Genetically speaking, the highvulnerability of genetic mutations and aberrantepigenetic regulations (such as loss of p53, the tumoursuppressor protein) are critical for cancer cells to envisionaggressive metastatic prospect.5Recent advances in bio-molecular techniques andextensive molecular and cellular digging have brought thediverse role of platelets (thrombocytes) in aiding cancermetastasis much in the limelight.6 Platelets are dynamicregulators of haemostasis. They are small, non-nucleuscellular fragments of megakaryocytes generated in thebone marrow. As a dominant player in haemostasis entity,their primary response to injured endothelium isattainment of adhesion to exposed sub-endothelialcollagen, platelet activation and degranulation andplatelet aggregation to attenuate haemorrhage.7Platelets, now widely accepted, are capable of multimodaltask beyond their well-appreciated part in haemostasis andthrombosis. They have been outlined to behave as a bridgebetween benign and malignant tumour, transmuting thepro-metastatic tumour to highly aggressive metastaticcancer. They faithfully ease the tumour cells tobreach cellularboundaries by successively limiting tumour cells to vascularcompartment, escaping immunological checkpoints andpotentiating invasiveness and eventually colonizing distanttissues. A key component is the releaseof 'biological vomitus';bioactive molecules from platelets which, importantly,includes the mitogenic and angiogenic factors. Bothmentioned factors are designed to enhance cellular andvascular proliferation, respectively with succeeding cancerexpansion over wide area of the body.8Tumour microenvironment ('pro-metastatic niche')represents an early and imperative step in the progressionof cancer by optimizing cellular environment in favour oftumour dissemination. For effective rooting, the molecularexchange of courtesies between the host and tumour cellsmust be constructive. Platelets have been revealed tosynchronize tumour microenvironment by engaginggranulocytes (leukocytes)using chemokine signalingmechanisms,marking the initiation of platelet contributiontowards malignant transformation. It has been furtherremarked that, whereas tumour cells have amplebiomolecules, tumour cell per se might not be efficient toattract granulocytes; making platelets of centralimportance to 'pro-metastatic niche'.9The transitional interval of tumour cells in vascularcompartment commences their first encounterwithplatelets.Tsuruo et al. proposed, in their review, that the vascularlongevity of tumour cells is indispensible for successfulhaematogenous seeding of cancer since they are vulnerableto extinction, owing to extreme straining of blood flow andimmunological destruction. In vitro experimental studieshave emphasized that platelet activation and aggregation ispivotal to cancer budding. Furthermore, their activation andaggregation is mainly procured by biologically activemolecules expressed on tumour cells surface such as tissuefactor (TF) and P-selectin ligands (adhesion molecules).Worthyofnote is the subsequent formationof 'platelet shield'(platelet cells-cancer cell adhesion) surrounding cancer cellsthat is central to immuneevasion; impedingnatural killer cellsJ Pak Med Assoc330EDITORIALEmerging protagonists in cancer metastasis: An oath of allegiance by plateletsAkbar Shoukat Ali,1 Arzoo Ajaz,2 Heeba Hamid31Department of Anaesthesiology, The Aga Khan University, Karachi, & Bachelorof Science in Nursing (BSN), Institute of Nursing, Dow University of HealthSciences, Ojha Campus, Karachi, 2,3Pharm D Students, Jinnah University ofWomen, Karachi, Pakistan.Correspondence: Akbar Shoukat Ali. Email: akber.shoukat.ali@gmail.commediated tumour lysis and potentiating attachment tovascular endothelium.9,10Growing body of evidence suggests that actively inducedexperimental thrombocytopenia significantly attenuatesmetastasis. A study by Camerer et al. used platelet deficient(genetically knocked out) mice and reported viablereduction in experimental metastasis load (94%). Anothersurfacing fact is the platelet releasate, emphatically plateletmicroparticles. Tumourigenesis is a complex molecularprocess and crucial to it are genetic mutations that allowcancer cells to undergo proliferation incessantly. A researchstudy documented that such molecular signals could bederived from platelet microparticles. Beyond aberrantcellular growth, platelet microparticles confer cancer cellswith the ability of highly orchestrated anti-apoptoticactivity; maintaining their everlasting survival.11,12Neovascularization (Angiogenesis) is a requisite for tumoursurvival and metastatic expansion. The cocktail of bioactive(pro-angiogenic) factors are encapsulated by platelets suchas platelet-derived growth factor (PDGF), vascularendothelial growth factor (VEGF), basic fibroblast growthfactor (bFGF), epidermal growth factor (EGF), hepatocytegrowth factor (HGF) and insulin-like growth factor (IGF),whereby they contribute to the development of tumourburden. Also, platelets have been linked to induce the pro-angiogenic factor expression by tumour cells.13-15The archetypes of cellular entities, notably cancer stem cells,perhaps in opposite to other non-tumourigenic tumour cellshave potential to engender new tumour and metastasisphenotype.Accumulatingevidenceshavedemonstrated thattumour cells are composed of assorted cell group involvingcellular subtypes with self-sufficiency in regeneration.Platelets also play a key role in assisting aforementionedgroup of tumour cells. Labelle and his colleague mentionedmorphological modifications consistent with epithelial tomesenchymal transition (EMT) in experimental plateletconditioned mouse colon (MC38GFP) and breast carcinomacell (Ep5) lines.Additionally, these findingswere further testedfor enhanced tumour invasiveness and appeared positive.9In conclusion, metastasis is a highly coordinated process andis compounded by the cascade of molecular and cellularevents. Early cognizance of tumour with metastaticdisposition is crucial for the foundation of adaptabletherapies to minimize the risk of metastasis associatedmortality. Platelets and their delivered substances areemerging as active regulators, mobilizing cancer stability andsubstantial metastasis. Rather, they have become evident asnew diagnostic, prognostic and therapeutic markers in thediscipline of bio-molecular oncology. Identification of'Mechanistic heterogeneity' of platelets to endorse canceradvancement is a growing concern which calls for additionalexperimental studies. Nevertheless, many such findings willhelpus indevisingnovel therapies to targetprecisemolecularsignature steps mediating cancer cell adhesion, migrationand proliferation; metastasis.Conflict of Interest:Nil.Financial Support:Nil.References1. Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST,Lai OS, etal. Cancer is a preventable disease that requires major life-style changes. Pharm Res. 2008; 25:2097-116.2. CancerResearchUK.Worldwidecancerstatistics [Online]2016[cited2016October 18]. Available from: URL: http://www.cancerresearchuk.org/health-professional/cancer-statistics/worldwide-cancer#heading-Zero3. World Health Organization. Cancer- Fact sheet. [Online] 2014 [cited2016 October 18]. Available from: URL:http://www.who.int/mediacentre/factsheets/fs297/en4. Lou XL, Sun J, Gong SQ, Yu XF, Gong R, Deng H. Interaction betweencirculating cancer cells andplatelets: clinical implication. Chin JCancerRes. 2015; 27:450-60.5. Vanharanta S, Massagué J. Origins of metastatic traits. Cancer Cell.2013; 24:410-21.6. Gay LJ, Habermann BF. Contribution of platelets to tumor metastasis.Nat Rev Cancer. 2011; 11:123-34.7. XuXR, ZhangD,Oswald BE, CarrimN,WangX, HouY, etal. Platelets areversatile cells: New discoveries in hemostasis, thrombosis, immuneresponses, tumor metastasis and beyond. Crit Rev Clin Lab Sci. 2016;53:409-30.8. Li N. Platelets in cancer metastasis: To help the "villain" to do evil. Int JCancer. 2016; 138:2078-87.9. Labelle M, Begum S, Hynes RO. Platelets guide the formation of earlymetastatic niches. Proc Natl Acad Sci U S A. 2014; 111:E3053-61.10. Tsuruo T, Fujita N. Platelet aggregation in the formation of tumormetastasis. Proc Jpn Acad Ser B Phys Biol Sci. 2008; 84:189-98.11. Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, CoughlinSR. Platelets, protease-activated receptors, and fibrinogen inhematogenousmetastasis. Blood. 2004;104:397-401.12. Wieczorek AJ, Wysoczynski M, Kijowski J, Marquez-Curtis L,Machalinski B, Ratajczak J, etal. Microvesicles derived from activatedplatelets induce metastasis and angiogenesis in lung cancer. Int JCancer. 2005; 113:752-60.13. Italiano JE, Jr Richardson JL, Patel-Hett S, Battinelli E, ZaslavskyA, ShortS, etal. Angiogenesis is regulated by a novel mechanism: pro- andantiangiogenic proteins are organized into separate platelet alphagranules and differentially released. Blood. 2008; 111:1227-33.14. Peterson JE, Zurakowski D, Italiano JE, Jr Michel LV, Fox L, Klement GL,etal. Normal ranges of angiogenesis regulatory proteins in humanplatelets. Am J Hematol. 2010; 85:487-93.15. Franco AT, Corken A, Ware J. Platelets at the interface of thrombosis,inflammation, and cancer. Blood. 2015; 126:582-8.Vol. 67, No. 3, March 2017Emerging protagonists in cancer metastasis: An oath of allegiance by platelets 331

Emerging protagonists in cancer metastasis: An oath of allegiance by platelets

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Emerging protagonists in cancer metastasis: An oath of allegiance by platelets

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