Angiogenesis in gastrointestinal stromal tumors:From bench to bedside

lNTRODUCTlON

Gastrointestinal stromal tumors (GISTs) are rare neoplasms with an estimated incidence from 0.78 patients to 2 patients

100000[1,2].Their highest prevalence is noted during the eight decade of age,when they affect up to 3.06 individuals

100000[3].GIST typically present as subepithelial masses mainly in stomach (60%) and small intestine (20%-30%) with omentum,mesentery and rectosigmoid areas being less-frequently involved areas[4].According to their primary location,GISTs could clinically present as gastrointestinal hemorrhage,anemia,dyspepsia or vomiting when the upper gastrointestinal tract is involved and as bowel obstruction,frequent urination or diarrhea in implication of the lower gastrointestinal tract[5].The metastatic disease principally concerns the liver,omentum,and peritoneum presenting as abdominal pain or constipation while extra-intestinal metastases to lymph nodes(LN) and lungs are infrequent[4].The pathological diagnosis relies on the tissue’s morphological and molecular characteristics.Based on their morphology,GISTs are classified into three groups according to the predominant cell type: Spindle cell type (70%),epithelioid cell type (20%) and a mixed type (10%).CD117 comprises a transmembrane protein which is the end-product of the

expression[6].The KIT(CD117) positivity in immunohistochemistry (IHC) in tissues which are morphologically consistent with GIST establishes the diagnosis in the 95% of the cases.In KIT negative cases,the discovered on GIST 1(DOG1) and CD34,which is an antigen of the myeloid progenitor cells,staining or the documentation of KIT or

(

gene mutations are sufficient to institute a diagnosis.Seldom in pediatric and young populations,GIST formation arises in the context of succinate dehydrogenase-deficiency in conjunction with paragangliomas and pulmonary chondromas[7,8].

The pharmacologic targeting of angiogenesis in cancer therapeutics was introduced as a groundbreaking approach.Nevertheless,the anti-vascular endothelial growth factor (VEGF) targeting alone or in conjunction with chemotherapy displayed only modest benefit in overall survival in solid tumors indicating the complexity of the mechanisms that regulate tumor angiogenesis[9].Thus,the necessity arose to develop a broad spectrum of anti-angiogenic treatments such as: Direct VEGFR2 antagonists(ramucirumab),VEGF-Traps (aflibercept),several receptor tyrosine kinases inhibitors targeting the PDGF-R,CD117 (c-KIT),fibroblast growth factor receptors (FGFR),epidermal growth factor receptor,RET,RAF kinases and the repurposing of drugs like the mammalian target of rapamycin inhibitors and lenalidomide[9,10].In fact,anti-angiogenetic therapy has gained ground in the management of advanced,unresectable disease.Imatinib,an abl,c-KIT and PDGF-R tyrosine kinase inhibitor (TKI),constitutes the empiric treatment when the mutational status of the disease remains unknown and the first line of treatment in KIT and PDGFRA positive metastatic,inoperable GISTs.The D842V mutation in

comprises a therapeutic exception and is being treated with avapritinib while

and

wild type tumors are treated with sunitinib or regorafinib[11].

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All the above mentioned drugs achieve,at least partially,their cytotoxicity disrupting signaling pathways which are implicated in angiogenesis,as it would be further analyzed below.This suggests that angiogenesis might be of paramount importance for the carcinogenesis process in GISTs and an attempt to summarize all the pre-clinical and clinical data would be of great value.

THE ROLE OF ANGlOGENESlS lN GlST’S DEVELOPMENT AND PROGRESSlON

The molecular mechanisms of angiogenesis in GISTs–preclinical data

The regulation of angiogenesis is necessary for cancer cells initially to cope with their increased metabolic needs and in the process to promote their metastatic potential.Its significance was firstly recognized by Folkman[12],which stated that the magnified rate of neovascularization compared with wound healing and inflammation as a result of an interplay between tumor cells and endothelial cells was a prerequisite in order to achieve tumor growth[12].Presently,it is widely known that the angiogenic process is being coordinated by the balance of several angiogenesis inducers and inhibitors in tumor’s microenvironment.The dominance of the pro-angiogenetic factors,a phenomenon called“angiogenic switch”[13],triggers the angiogenesis and could result either as result of the consequent hypoxia from the increased tumor proliferation or by the immune cell infiltration[14].The primary induction phase with the undeveloped vessels paves the way for the remodeling phase when the blood vessel generation is sustained[15].Several models of angiogenesis have been described explaining partially the poor outcomes of the selective angiogenic blockage as certain tumors can utilize alternative modes of angiogenesis[14].Their analytical presentation has been done elsewhere[14,16,17] and goes beyond the scope of this review but a brief presentation in

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Table 1 would be helpful.

Xenograft studies in mice constitute an invaluable source of evidence about the angiogenetic mechanisms in GISTs.Our fundamental conceptualization about the orchestration of the angiogenetic process descended from Giner

[18].They utilized an intensely CD117,DOG1 and CD34-positive GIST with continual Ki-67 expression in about 15% of the tumor’s mass.The neovascularization experiments demonstrated the propagation of the induction phase during the first 96 h after implantation which proceeded by the remodeling phase.The induction phase was guided by the

,

,

,

gene expression in conformity with their receptors.In more detail,the IHC data indicate that the VEGF ligand and the VEGFR2,VEGFR3 were positive at day 4 after the xenografting.As regards the chemokine expression,CXCL9,CXCL10,GRO and their receptors CXCR3,CXCR2 were stained in tumor cells and stroma soon after the implantation with a slight staining predominance of the chemokine receptors.These effects are possibly orchestrated by hypoxia-inducible factor (HIF)1α and the CXCL12/CXCR4 axis,which are constantly expressed[18].

All the authors report no relevant conflicts of interest for this article.

Furthermore,while the contribution of epigenetic mechanisms in the GIST progression is well established,its impact in the angiogenetic mechanisms could be further delineated.Several gaps in our understanding that remain unaddressed by the subdivisions according to the driver gene mutation status could be further elucidated by the tumor’s epigenetic landscape.The alterations in the tumor’s methylation profile are associated with a more aggressive phenotype[28] and the methylation status of the CD133 could reshape the management of the disease and it would be presented below in more depth[29].The KDM4 family members (KDM4A-D) reshaping the structure of chromatin are implicated in the pathogenesis of a wide variety of cancers[30].In GIST,the upregulation of KDM4D potentiates the angiogenesis in vivo,as indicated by the overexpression of CD31 in IHC.These effects are mediated by the HIF1β/VEGFA pathway in the presence of demethylation in the promoters of the

and

genes[31].

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The association between imaging data and angiogenesis in GISTs

As highlighted above,angiogenesis mediates an extensive proportion of GIST’s malignant dynamics.Several signaling pathways are implicated in the regulation of angiogenesis such as: The VEGF,the fibroblast growth factor-2 (FGF2),the PDGF,the angiopoietins,the Eph/ephrin signaling,the Apelin/APLNR pathway,the HIFs and several chemokines[14].The VEGF signaling comprises the most wellstudied pathway in GIST angiogenesis.

The development of biomarkers comprises an essential step towards the individualization of medical practice.Liquid biopsy provides a cutting-edge,non-invasive technology to access predictive information to guide the therapeutic management in a wide variety of diseases[47-51].It’s application in GIST treatment has been started to emerge[52,53].Reviewing subsequent and more recent literature,an extensive number of studies has been found associating molecules implicated in angiogenesis with pathologic features.Although there are several limitations in the above mentioned research,theimportance of angiogenesis in GIST’s malignant progression is delineated.In

The utilization of EUS has emerged during the last decades.Its ability to evade the intervention of the abdominal fat and gastrointestinal gas in conjunction with the capability of FNA biopsy render it a useful tool towards a more personalized approach in the management of GIST.In EUS the GISTs are visualized as hypoechoic masses arising from the muscularis propria or the muscularis mucosae.The presence of irregular margins,cystic areas or malignant LN herald bad prognosis[44].The usage of contrast media enhances further the diagnostic capacity of the EUS and promotes the tumor’s vascularity as a valuable prognostic biomarker.The role of CE-EUS in the management has been extensively reviewed elsewhere[45] and we intend to delineate the fundamentals.Sakamoto

[39]classified the tumor’s vascularity into two subgroups according to the pattern of perfusion (homogenous or heterogeneous) and vessel appearance (regular or irregular).The homogenous perfusion with regular vessels were considered as signs of mild clinical behavior.Furthermore,they compared the diagnostic sensitivity of contrast-enhanced harmonic US,Power-Doppler EUS and CE-multidetector CT to visualize tumor vessels.In GISTs larger than 3 cm their sensitivities were 100%,75% and 42%respectively.The differences became more emphatic in tumors less than 3 cm: 100%,25% and 0%,respectively.It was noteworthy that every malignant lesion less than 3 cm in the cohort had been detected by the CEH-EUS before surgery[39].The above indicate that CE-US comprises a powerful tool to visualize vascularity.Taking a step further,Yamashita

[46] demonstrated an association between the imaging findings on CE-US and the pathologic risk stratification.In more depth,the large vessels lacked elastic tissue,indicating that neovascularization constitutes the underlying pathogenetic mechanism,and expressed VEGF[46].

It becomes evident that the imaging findings of vascularity might be sensational and practice changing in a subset of patients with small sized tumors (＜ 3 cm) and aggressive phenotype.A more substantial body of evidence should be collected in order to address properly those dilemmas.

Angiogenesis mediators as biomarkers in GIST–clinical data

The above mentioned gap was attempted to be filled by a landmark study by Iannicelli

[40],the computed tomography (CT) constitutes the fundamental imaging modality in patients presenting with the clinical manifestations of GIST.Reviewing past literature,several studies have documented that aim to associate certain imaging features with pathologic parameters[41,42].Iannicelli

[40] presented that GISTs with irregular margins tended to have superior mitotic rate than tumor with regular margins.Furthermore,a heterogonous pattern of contrast enhancement (CE),the angiogenesis and necrosis correlated with an increased tumor size and a more aggressive clinical behavior.It worth mentioning that the intensity of CE although it represents a novel mark of biologic activity,was not correlated with neither the number of mitoses nor the tumor’s risk stratification[40].The above comprise an indirect link between tumor’s margins and mitotic rate,which is essential in order to stratify before surgery the clinical behavior of the tumor and highlight the importance of angiogenesis in disease progression.The latter could also be deduced by dynamic positron emission tomography analysis.Strauss

[43] reported an association between the rate in which the F-18-fluorodeoxyglucose diffused into the tumor with the expression of VEGF-A[43].The main limitation of CT comprises it’s low sensitivity as regards the imaging of vascularity in small sized tumors[39].This divergence could be addressed by the endoscopic ultrasound (EUS) technology.

Table 2 are summarized the most significant data.

CONCLUSlON

There have been several classification systems to stratify the malignant potential of GISTs such as: The National Institutes of Healthv consensus criteria (Fletcher's criteria),the Armed Forces Institute of Pathology criteria (Miettinen's criteria) or the International Union against Cancer TNM classification.Their main drawback constitute the inability to validate the tumor’s aggressiveness without surgical resection and detailed pathologic examination of the entire tumor to estimate the mitotic count[37,38] .Although taking into consideration the current therapeutic trends,the management of the advanced,unresectable disease is unequivocal,there are margins for improvement in the management of primary localized disease,especially in small-sized tumors.It could not be emphasized enough that even small GISTs could develop malignant behavior.Thereat,it could provide us a wealth of valuable predictive and prognostic information an attempt to incorporate imaging data about the vascularization of the tumor such as the vessels’ irregularity or the blood perfusion[39].

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Finally,it is worth mentioning that several multi-TKIs exert their anti-tumor efficacy at least partially by the inhibition of angiogenesis.Cabozantinib exerts it’s activity inhibiting the receptor tyrosine kinases MET,VEGFR2,Flt-3,c-Kit and RET[32,33] while sorafenib inhibits the signaling of VEGFR-1,VEGFR-2,VEGFR-3,PDGFR-β,Flt-3,c-Kit and the Raf serine/threonine kinases[34].Both diminish the tumor’s microvascular density as evidenced by CD31 IHC[35,36].

Papadakos SP and Tsagkaris C contributed equally; Papadakos SP and Tsagkaris C contributed to the onceptualization and study design; Papadakos SP wrote the first draft; Moysidis DV,Papazoglou AS,Papadakis M and Zografos CG wrote the second draft; Tsagkaris C,Papadakis M and Theocharis S contributed to the critical revision; Papadakis M and Theocharis S contributed to the supervision

The angiogenetic process in GIST has been further delineated and several regulatory molecules have been identified.CCL2 represents a chemokine expressed by the tumor cells to attract CCR2-expressing endothelial progenitor cells from the circulation as documented in HER-2/neu-driven breast cancer[19].On the other hand,the VEGF-induced nuclear factor kappa B (NF-kB) upregulation is frequently utilized to attract inflammatory cell into tumor to stimulate the angiogenesis[20].The bromodomain and extraterminal domain family mediates immunity regulating several signaling pathways[21].In GISTs,the BRD4 upregulation enhanced the migratory and invasion processes regulating angiogenesis through the NF-kB/CCL2 signaling pathway.The BRD4-expressing cells attract tumor-associated macrophages

the expression of CCL2 potentiating the tumor’s microvessel density and secrete various proangiogenic molecules such as VEGFA,LOX and MMP9[22,23].Towards the same direction,mutations of the protein phosphatase 2,regulatory subunit A,alpha (PPP2R1A) affect the carcinogenesis process[24,25].In GISTs,mutations in

gene are found in nearly 20% of the cases and correlate with a more aggressive tumor phenotype.They result in increased growth rate

enhancing phosphorylation of c-kit,Akt1/2,ERK1/2 and WNK1.The latter seems to mediate the regulation of the angiogenetic process[26,27].A further analysis of the specific mechanisms would be of great value and it should be applied.

The FGF2/R2 signaling has been extensively studied in GIST as a drug resistance mechanism.Sergei

[54] and Boichuk

[55] demonstrated that the blockage of FGFR2 signaling could enhance the responsiveness to DNA-Topoisomerase II inhibitors[54] while the downregulation of FGF2 signaling might stimulate the response to imatinib[55].It’s contribution in GIST progression has been reviewed[56] but data about potential effects in GIST vascularization process are missing.Towards the same direction,the Eph/ephrin system has been investigated in carcinogenesis[57,58].It would be of paramount importance an attempt to outline its contribution in GIST angiogenesis.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

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Stavros P Papadakos 0000-0003-1583-1125; Christos Tsagkaris 0000-0002-4250-574X; Marios Papadakis

0000 -0002-9020-874X; Andreas S Papazoglou 0000-0003-4981-8121; Dimitrios V Moysidis 0000-0001-9083-0267;Constantinos G Zografos 0000-0002-8203-6407.

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Fan JR

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