Thrombosis and Cancer:Apersonalview
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©2007 Schattauer GmbH,Stuttgart AnniversaryIssueContribution Thrombosis and cancer:Apersonalview 1957–2007) Maria BenedettaDonati y( Research Laboratories, “JohnPaul II” Centrefor High Te chnologyResearchand Education in Biomedical Sciences, CatholicUniversity, Campobasso,Italy uring our Ph.D.studiesatthe LaboratoryofMarc Ver- cells (18),aswellasindifferent humantumors (19).Itwas also straete, under the guidance of JosVermylen (Leuven Uni- the main procoagulant activity of acutepromyelocytic leukae- Anniversar D versity),Giovanni de Gaetano and myself went to visit mia,and asensitive marker of both diseaseactivity and response th some US laboratoriesin1972, including that of Eugene Cliffton to chemotherapyand ATRA treatment (20–22). Cancer pro- 50 at Sloan Kettering in NewYork. This investigator wasindeedone coagulant had been purified fromhuman amniochorial or sev- of the pioneers to propose the two-way association between eral malignant tissues as acysteine protease with apeculiarclot- thrombosis and cancer. ting mechanism by Anna FalangainGordon’sLaboratory. Des- This association, described one century earlierbyArmand pite theeffortofseveral laboratoriesinthe past 20 years,such an Trousseauintumors of the gastro-intestinaltract (1), had not important tumor cell procoagulant and malignancymarker,for a beenfurther explored, butwarrantedboth experimental and number of reasons including technicalproblems, hasnot receiv- clinicalattention,asCliffton’s work had showninthe 1960s ed so faracomplete molecularand genetic characterization, (2–6). whichremains open to future research. Back to Italyin1973, we were asked to openanew laboratory Studies in experimental models of tumor growth ledustothe on haemostasis and thrombosis in Milan at Mario NegriInsti- definition of the type of thrombocytopenia and anaemia associ- tute,anon-profit researchinstitution well known at thattime for atedwith the growth of the primary site in some murine tumors its experimental studies in the fieldofcancer chemotherapy. We (10, 11) and to the discoverythat warfarin could exertapeculiar decided therefore to match the experienceinthe physiopathol- antimetastatic effect in some models, possibly due to the in- ogyofhaemostasis and thrombosis –gained during ourMD hibition of cancerprocoagulant, characterized as anovel vitamin studiesatRome CatholicUniversity with Raffaello Breda and K-dependent factor (16, 17,24). Other studies in mice, with Ni- BrunoBizzi,two pioneers of coagulation studies in Italy,and ex- cola Semeraro, Alberto Mantovani, Mario Colucciand Roberto tendedduring our five years spent at the Leuven Laboratory– Lorenzet, led us to realize howimportant tumor/hostinteractions withthe experienceofMarioNegri Institute investigatorsinthe were in the expression of a“physiological”extravascularpro- oncologicalfield. coagulant suchastissue factor (TF)with consequent fibrin de- We started to work there at twolevels: cellbiology,looking position at the tumor/host interface(25, 26). These studies pion- with Luciano Morasca at the procoagulant/fibrinolytic activities eeredalarge seriesofexperiments on inflammation, cancerand of tumors cells (7–9) and animal models, with Andreina Poggi, host antitumor defencemechanisms. looking at changes in the haemostatic system of the host during Despite the progress ourgroupand fewothers had accom- the development of some experimental tumors (10, 11) and on plished in the field, the association of thrombosis and cancer was the treatment of murine tumors with antithromboticdrugs mainlyconsidered, till the end of the 1970s, the concernofsome (12–14). “exoteric” investigatorsand the presentations proposedathae- mostasis and thrombosis meetings were regularlyranked as Acancer procoagulant “other”or“miscellaneous”. As theywere notincludedinany major category, theywere usually accepted as posters, to be pres- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Many studieswere focussedonanew procoagulant activity spe- ented during the less important sessions.Ahonourableexception cificallyconfined to the malignant phenotype,the so-called wasthe 1979 Congress of the InternationalSociety onThrombo- “CancerProcoagulant”.This factor appeared to be similartothe sis and Haemostasis (ISTH) in London, where the late Arthur one describedinrabbitV 2 carcinoma by StuartGordon’sgroupin Bloom organizedasymposium on “Malignancyand Haemosta- Denver, Colorado,and wasfound by our group in several warfa- sis”, Iwas askedtochair togetherwith JohnDavidson(27). The rin–sensitive murine tumors(9, 16, 17) and in human melanoma increasing interest of our group into “cellular aspects of haemos- Correspondence to: Received May22, 2007 Maria B. Donati Accepted May23, 2007 ResearchLaboratories “John Paul II” Centrefor High Te chnologyResearch Prepublished onlineJune 12, 2007 and Education in Biomedical Sciences doi:10.1160/TH07–05–0363 Catholic University C. da Tappino,86100 Campobasso, Italy ThrombHaemost 2007; 98: 126–128 Te l.: +390874 312278, Fax: +39 0874 312710 E-mail: [email protected] 126 Donati: Thrombosis andcancer tasis”,was also reflected by the “BizzozeroSymposium” organ- The development of low-molecular-weightheparins izedtogether with PeterMannucci in Bergamo(1982) on the oc- (LMWH) in the prevention/treatment of thrombosis in cancer casion of the 28th ISTH SubCommitteemeeting. patients, haslatelymade availableamore patient-friendlyanti- In 1983,within the ISTH, we succeeded in establishinganew thrombotic treatment in these patients. The favourableexperi- SSC SubCommitteedevoted to “Malignancyand Haemostasis”. encewith LMWHopenedindeedthe waytonew trials with he- Its first chairman wasYaleNemerson.Itook the chair in the sub- parins to modify the natural historyofseveral tumors(42, 43). sequent years (1985–1988), followedthen by Graham Jamieson, This happened during the last fewyears and is still goingon. 1957–2007) Fred Rickles, Mark Levine, Ajay Kakkar,Anna Falangaand From preliminarydataavailableinthe first trials (44-47)it Martin Prinz (2007).These SubCommittee meetings gradually would appear that LMWH treatment could delaymetastasis y( movedfrom 20–30attendees to over 300. growth in different tumors, butonlyifthe tumor is still at an early stage. This finding, confirmed by trials with different design and From experimental models to clinicaltrials treatment schedules(44–47), maybeexplained by the following hypothesis: LMWH would actonthe dissemination of tumor The real switchwas determinedbythe growing interest of clini- cells by anti-adhesive/anti-inflammatoryproperties(different at Anniversar cal oncologists in the association between thrombosis and least in partfrom their anticoagulant activity);these properties th cancer,along twomainlines: would enableLMWHtoprevent the adhesion of tumor cells to 50 –The association of thrombosis with cancertreatment,not the vascularwalland their extravasation to formmetastatic foci. onlysurgery, butchemotherapyand hormone therapyas Once metastases have beenformed,however,LMWHwould be well. This concernhas lately beenextendedtothe risk of unable to prevent their growth. Forthis reason onlytumors at a thrombosis associated with anti-angiogenic therapy(28–31). relativelyearlystage,i.e. with still asignificant burden of circu- –The observation of idiopathicorunprovokedvenous throm- lating tumor cells, would respond to the inhibitoryordelaying bosis as apredictorofthe clinicalmanifestation of an occult effectsofLMWH. This hypothesis is supported by recent in- cancer (32–34). vitrodatashowing the ability of some LMWH to prevent cell- cell interactions, relevant for the adhesion of cancercells to the Thesetwo clinical issueshaveprompted newresearch and in- vascularwalland subsequent extravasation (48,49). Old experi- spired experimental work in the last fewyears.Meanwhile,the mental work in micehad alreadyshown the best timewindowof work of the SubCommitteehad ledtothe establishment, in col- treatment with heparintoobtain an anti-metastatic activity: This laboration with LeoZacharski, of aRegistryofClinical Trials of effect wasindeedonlyobservedwhen tumor cells were injected Antithrombotic Drugs in cancer patients, first publishedin1989 intravenously in micepretreated with heparin(40). (35) and updatedin1993 (36).The Registry clearlyshoweda very messy situation in aperiod when, in otherfields suchasthe Conclusions cardiovascularone, the application of modernclinical trialmeth- odologyhad allowedtoreach important goals for prevention and The relationships betweenthrombosis and cancerare aparadig- treatment of ischaemic heart disease (37–38). matic exampleofthe useful cross-talk betweenexperimental Indeed,atthe experimental level, evidencehad been col- data and clinicalresults: many years after the reportsonbenefi- lected to suggest thatmodification of the host’shaemostatic sys- cial heparineffectsinexperimental tumor models (4, 5), recent tembydifferent pharmacological approaches could lead to clinicalresults (44–47) promptedustogoback to experimental changes in the degree and speed of tumor and metastasis growth systems, to find out the best conditions for heparin to favourably (12–14). Thedatacould be schematicallysummarized as fol- modifythe natural historyofsome human tumors. Presently, lows: Whateverantithrombotic drug or condition, such as anti- these studiesneed to carefullyconsider the mechanism of hepa- plateletantibodies or dysfunctional platelets, would reduce rin’saction in relation to both tissue factor expression by cancer blood