http://clincancerres.aacrjournals.or...ull/13/22/6850
Letters to the Editor
Zoledronic Acid and Angiogenesis
Gianluigi Ferretti, Alessandra Fabi, Paolo Carlini, Paola Papaldo, Alessandra Felici, Silverio Tomao and Francesco Cognetti Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy
To the Editors: In a recent issue of
Clinical Cancer Research,
Santini and co-workers (
1) assert that zoledronic acid (ZA)
may inhibit several antiangiogenic-related cascades and its
metronomic administration could represent a new potential therapy
targeting the endothelial-tumor-stroma behavior. We agree with
the authors because better targeting of ZA to cells outside
bone could more likely be achieved by more frequent administration
of low doses. Thus, metronomic ZA administration could lead
to significant intracellular accumulation over time in tumor
cells (
2).
In cervical tumors, the antineoplastic responses due to impaired
angiogenesis and reduced vascularity could result in part from
the targeting of matrix metalloproteinase (MMP)-9. MMP-9 could
mobilize vascular endothelial growth factor (VEGF) and increase
its association with VEGF receptor-2. ZA suppresses MMP-9 expression
by tissue-infiltrating macrophages and inhibits its activity,
reducing association of VEGF with its receptor on angiogenic
endothelial cells (
3). In mice, a combinatorial regimen involving
a MMP inhibitor along with metronomic chemotherapy produced
regression and survival benefit against large end-stage pancreatic
tumors. On the other hand, ZA can also directly inhibit proliferation
of the angiogenic endothelial cells. Bisphosphonates, however,
have been used in animal models at high doses, which are not
comparable with the clinical dosing regimens used for the treatment
of cancer patients with skeletal metastases (
4).
With regard to the ability of ZA to inhibit MMP-9, it is worthwhile
noting that MMP-9 is involved in mobilization of circulating
endothelial progenitor cells and hematopoietic stem cells from
the bone marrow. MMP-9 induced in bone marrow cells causes the
conversion of Kit ligand from a membrane-bound, adhesion/survival-promoting
molecule to a soluble survival/motogenic molecule, releasing
soluble Kit ligand and permitting the transfer of endothelial
and hematopoietic stem cells from the quiescent to proliferative
niche (
5). Release of soluble Kit ligand by MMP-9 enables bone
marrow repopulating cells to translocate to a permissive vascular
niche, favoring differentiation and reconstitution of the stem/progenitor
cell pool. The mobilization of both hematopoietic stem cells
and VEGF receptor-2–expressing circulating endothelial
progenitor cells to the circulation occurs in response to VEGF
and is MMP-9 dependent (
5). MMPs and the VEGF/VEGF receptor-2
system are responsible not only for the formation of the dense
vascular network but also for the recruitment and infiltration
of bone marrow–derived macrophages. Depleting tumor-associated
macrophages and tumor-associated dendritic cells, however, does
not eliminate other stromal sources of proangiogenic mediators
(i.e., mast cells, neutrophils, fibroblasts, other dendritic
cell subsets, and possibly pericytes). For this reason, tumor-associated
macrophage depletion remains an adjuvant treatment that has
to be combined with chemotherapy or radiotherapy.
References
- Santini D, Vincenzi B, Galluzzo S, et al. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res 2007;13:4482–6.[Abstract/Free Full Text]
- Ferretti G, Fabi A, Carlini P, Papaldo P, Felici A, Cognetti F. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. Bone 2007;41:155–6.[Medline]
- Giraudo E, Inoue M, Hanahan D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 2004;114:623–33.[CrossRef][Medline]
- Clézardin P, Ebetino FH, Fournier PGJ. Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. Cancer Res 2005;65:4971–4.[Abstract/Free Full Text]
- Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002;109:625–37.[CrossRef][Medline]
Related Article
Zoledronic Acid and Angiogenesis Daniele Santini, Bruno Vincenzi, and Giuseppe Tonini
Clin. Cancer Res. 2007 13: 6850-6851. [Full Text] [PDF]