Page 2080 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 123 The Blood Vessel Wall 1849

proteolytic clips that release the Notch intracellular domain, which fibronectin, collagen type IV α3 chain (tumstatin), and collagen type
then translocates to the nucleus where it effects transcriptional activa- XIII (endostatin), as well as coagulation protein fragments such as
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tion via the DNA-binding protein CSL (also called RBP-Jκ or plasminogen (angiostatin) and antithrombin. The mechanism of
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CBF1). Gene targeting studies have revealed a critical role for action of these protein fragments depends on the particular polypep-
Notch1, Dll1, Dll4, and Jagged1 in vascular development and tide, but the functional effect usually is inhibition of endothelial pro-
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remodeling. Dll4–Notch1 signaling between endothelial cells liferation or induction of apoptosis. 173–175 Other endogenous inhibitors
within the angiogenic sprout serves to restrict tip cell formation in include interferons, chemokines, and interleukin-12 (IL-12).
response to VEGF. 160–162 Consequently, inhibition of Dll4 in adult More than 100 compounds are in clinical trials attempting to
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mice results in increased endothelial proliferation, sprouting, and cause regression of tumors by inhibiting angiogenesis. These
branching and increased tumor vascularity. 163,164 However, the vascu- compounds can be broadly divided into those that act directly by
lature is disorganized and poorly perfused; thus Dll4 blockade inhibits targeting the angiogenic endothelial cell and those that act indirectly
tumor growth in several models. 163,164 by targeting activators of angiogenesis. The latter category includes
targeting of oncogenes (e.g., mutant EGFR or Her2) because many
Coagulation Factors aberrantly activated oncogenes have been shown to induce expression
Tissue factor (TF) is a member of the cytokine receptor superfamily. of angiogenic factors. The first clear-cut evidence of efficacy in clinical
In addition to its role in initiating coagulation as a cofactor for factor trials of an angiogenic inhibitor for tumor therapy came from regi-
VII, TF may be involved in intracellular signaling. TF knock-out mens directed against the VEGF pathway (e.g., bevacizumab). 177,178
mice have abnormalities of their large vessels and microvasculature Because of the short improvement in overall and progression-free
secondary to defects in mesenchymal cell and periendothelial cell survival with the addition of VEGF inhibitors over standard chemo-
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accumulation and function. Elevated TF expression in various therapy, it is likely that heterogeneity and inherent instability of
tumors and the associated angiogenic endothelium has been tumor cell populations result in the selection of malignant cells that
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reported. Expression of mutant oncogenes (K-ras, EGFR) or tumor feed their vasculature through factors other than VEGF. In this
suppressor genes (PTEN, p53) leads to increased TF expression and regard, use of indirect angiogenic inhibitors still suffers from the
activity, and this may link tumor angiogenesis and the hypercoagu- likelihood of tumors becoming resistant to the therapy.
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lable states manifested in cancer. Abnormal development of the Whether the mechanism of action of these inhibitors is truly
vasculature also affects 50% of mice that are deficient in factor V. caused by the abrogation of a functional vascular supply is an open
The affected mice die in utero, and the 50% embryonic lethality is question. VEGF inhibitors “normalize” the aberrant, leaky tumor
similar to that observed in thrombin receptor–deficient mice that die vasculature. Other than in renal cancer, VEGF inhibitors have shown
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without obvious coagulation defects. Factor V–dependent genera- effect only when used in combination chemotherapy regimens, which
tion of thrombin may be important for early vascular development has led to the proposal that VEGF pathway inhibition improves vessel
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by signaling through the thrombin receptor. Thrombin can functionality and perfusion, thus facilitating delivery of chemothera-
promote angiogenesis through a mechanism that is independent of peutic agents. 177,178 VEGF–VEGFR signaling also acts in an autocrine
fibrin formation. 167,168 Studies have suggested that thrombin can fashion within some tumor cell populations, raising the possibility
stimulate release of angiogenic factors (e.g., VEGF-A) from tumor that positive outcomes may have as much to do with direct tumor
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cells and platelets, as well as induce VEGFR-2 on endothelial cells. kill as with an antiangiogenic effect. Finally, as with organogenesis,
In addition, APC and protein C inhibitor have been shown to con- the vasculature may provide a juxtacrine or paracrine role in support-
tribute not only to the regulation of hemostasis but also to cell ing tumor viability and proliferation independent of the provision of
inflammation, proliferation, apoptosis, tumor biology, and angiogen- a circulatory system for delivery of nutrients and oxygen. 53
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esis. Regarding angiogenesis, APC increases proliferation of vascular Some of the more common side effects observed with use of
endothelial cells and angiogenesis by APC receptor-mediated activa- VEGF-A inhibitors were not predicted a priori but may be under-
tion of mitogen-activated protein kinase, phosphatidylinositol standable in retrospect. For instance, hypertension and arterial
3-kinase, and endothelial nitric oxide synthase (eNOS) pathways. 170 thrombosis are common side effects. Two possible reasons may explain
Clinical trials have revealed that treatment with low-molecular– the hypertensive side effect. One is that VEGF directly activates eNOS
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weight heparins improves the survival time of cancer patients receiv- and thus may be responsible in part for basal production of NO.
ing chemotherapy, an effect that appears to be independent of the Another potential explanation is that podocyte-derived VEGF is
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anticoagulant properties of the low-molecular-weight heparins. 171,172 required for proper glomerular function throughout life. Heterozy-
Although antiangiogenic effects of specific heparanase-generated gous loss of podocyte VEGF results in hypertension and proteinuria
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fragments of unfractionated heparins have been demonstrated in in adult mice. Given that proteinuria is also commonly seen in
vitro, the mechanism of the antitumor effect remains to be defined. patients treated with VEGF inhibitors, the latter explanation would
The potential involvement of fibrinolytic factors in angiogenesis tie two of the side effects seen. The reasons for arterial thrombosis are
has been mentioned. Interestingly, fragments 1 and 2 of prothrombin less obvious. Because arterial circulation is more dependent on VEGF,
have been reported to inhibit angiogenesis, and various other frag- it is possible that arterial endothelial apoptosis serves as a nidus for
ments of coagulation and fibrinolytic proteins also may inhibit localized activation of coagulation and platelet aggregation. Apoptotic
angiogenesis. 173 endothelial cells have been shown to increase thrombin-generating
capacity and bind to unactivated platelets and leukocytes. 180–182
Other Factors More recently, the use of PDGF inhibitors to target pericytes has
Various other families of ligand–receptor pairs play a role in angio- been shown to be a potentially effective antiangiogenic strategy,
genesis. They include ephrin–Eph, Wnt–frizzled, neuropilin– particularly in combination with antiendothelial (anti-VEGF) mol-
semaphorin, slit–Robo, and sonic hedgehog–patched/smoothened. ecules. 96,98 “Metronomic” or low-dose, frequent scheduling of tradi-
Various chemokines have been shown to modulate angiogenesis in tional cytotoxic agents also is reported to have an antiangiogenic
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either a positive or negative fashion. effect and has proven efficacious in animal studies. Antivasculo-
genic therapy directed against recruitment of BM-derived vascular
precursors may have a role in future cancer therapeutic regimens, but
Inhibitors of Angiogenesis thus far the evidence is weak at best. 79

As with the angiogenesis inducers, multiple factors have been reported
to negatively regulate vascular morphogenesis. 88,173 Of interest is a class Arteriogenesis
of endogenous angiogenesis inhibitors that are fragments of larger
proteins that have little or no angiogenesis-related activity in their Arteriogenesis is a term coined to distinguish the development of
intact form. They include fragments of ECM proteins such as collateral vessels in adults from the process of angiogenesis. 184,185