Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis
may stop tumor growth, but vascular endothelial growth factor inhibitors have limited
effect in most tumors. This limited effect may be explained by an additional, less
vascular endothelial growth factor–driven form of angiogenesis known as intussusceptive
angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not
known. Epifluorescence and confocal microscopy was used to visualize intravascular
pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human
malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX),
and genetically engineered v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-induced,
phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)-deficient (BPT) mice
(BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and
PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression
and T-cell and macrophage infiltration in tumor sections were determined with multiplex
immunostaining. Intravascular pillars were detected in human metastases but rarely
in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases
compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages
and T-cells were detected in proximity to intravascular pillars. MMP inhibition blocked
formation of pillars, but not tubes or tip cells, in vitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human
melanoma metastases. MMP inhibition blocked pillar formation in vitro and should be further investigated as a potential anti-angiogenic drug target in
metastatic melanoma.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The American Journal of PathologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Tumor angiogenesis: therapeutic implications.N Engl J Med. 1971; 285: 1182-1186
- Angiogenesis in life, disease and medicine.Nature. 2005; 438: 932-936
- Antiangiogenic therapy: impact on invasion, disease progression, and metastasis.Nat Rev Clin Oncol. 2011; 8: 210-221
- Modes of resistance to anti-angiogenic therapy.Nat Rev Cancer. 2008; 8: 592-603
- Intussusceptive angiogenesis: a biologically relevant form of angiogenesis.J Vasc Res. 2012; 49: 390-404
- “Sprouting angiogenesis”, a reappraisal.Dev Biol. 2012; 372: 157-165
- Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis.Microvasc Res. 1977; 14: 53-65
- VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.J Cell Biol. 2003; 161: 1163-1177
- Intussusceptive angiogenesis--the alternative to capillary sprouting.Mol Aspects Med. 2002; 23: S1-S27
- Scanning electron microscope study of the developing microvasculature in the postnatal rat lung.Anat Rec. 1986; 216: 154-164
- A novel mechanism of capillary growth in the rat pulmonary microcirculation.Anat Rec. 1990; 228: 35-45
- A new mechanism of blood vessel growth - hope for new treatment strategies.Discov Med. 2009; 8: 23-27
- Inflammation-induced intussusceptive angiogenesis in murine colitis.Anat Rec (Hoboken). 2010; 293: 849-857
- Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells.Angiogenesis. 2013; 16: 921-937
- Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020; 383: 120-128
- Morphological characterization of sprouting and intussusceptive angiogenesis by SEM in oral squamous cell carcinoma.Scanning. 2014; 36: 293-300
- Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing's sarcoma A673-xenograft growth and normalize tumor vascular architecture.Angiogenesis. 2012; 15: 685-695
- Lack of angiogenesis in experimental brain metastases.J Neuropathol Exp Neurol. 2011; 70: 979-991
- Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation.Am J Pathol. 2008; 173: 1173-1185
- A new mechanism for pillar formation during tumor-induced intussusceptive angiogenesis: inverse sprouting.Am J Pathol. 2011; 179: 1573-1585
- Angiogenesis in malignant melanoma.J Dtsch Dermatol Ges. 2015; 13: 125-136
- Targeting angiogenesis in melanoma: prospects for the future.Ther Adv Med Oncol. 2010; 2: 367-380
- Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions.Oncotarget. 2014; 5: 9609-9618
- Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.Nat Genet. 2009; 41: 544-552
- Antioxidants can increase melanoma metastasis in mice.Sci Transl Med. 2015; 7: 308re8
- Filter-dense multicolor microscopy.PLoS One. 2015; 10: e0119499
- A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma.Cell Death Dis. 2018; 9: 810
- Supporting clinical decision making in advanced melanoma by preclinical testing in personalized immune-humanized xenograft mouse models.Ann Oncol. 2020; 31: 266-273
- STAR: ultrafast universal RNA-seq aligner.Bioinformatics. 2013; 29: 15-21
- GENCODE: the reference human genome annotation for the ENCODE Project.Genome Res. 2012; 22: 1760-1774
- Disambiguate: an open-source application for disambiguating two species in next generation sequencing data from grafted samples.F1000Res. 2016; 5: 2741
- HTSeq--a Python framework to work with high-throughput sequencing data.Bioinformatics. 2015; 31: 166-169
- A model of intussusceptive angiogenesis.Novartis Found Symp. 2007; 283 (discussion 42-45, 238-241): 37-42
- Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.Genome Biol. 2014; 15: 550
- Intussusceptive angiogenesis: its role in embryonic vascular network formation.Circ Res. 2000; 86: 286-292
- Intussusceptive microvascular growth, a new mechanism of capillary network formation.EXS. 1992; 61: 32-39
- Intussusceptive microvascular growth in human glioma.Clin Exp Med. 2010; 10: 93-98
- Microvascular density, vascular endothelial growth factor immunoreactivity in tumor cells, vessel diameter and intussusceptive microvascular growth in primary melanoma.Oncol Rep. 2005; 14: 81-84
- Angioarchitecture and CD133 + tumor stem cell distribution in intracranial hemangiopericytoma: a comparative study with meningioma.Neural Regen Res. 2011; 6: 2687-2693
- Consensus guidelines for the use and interpretation of angiogenesis assays.Angiogenesis. 2018; 21: 425-532
- Intussusceptive angiogenesis: its emergence, its characteristics, and its significance.Dev Dyn. 2004; 231: 474-488
- Microvascular growth, development, and remodeling in the embryonic avian kidney: the interplay between sprouting and intussusceptive angiogenic mechanisms.Microsc Res Tech. 2005; 66: 275-288
- Intussusceptive angiogenesis and its role in vascular morphogenesis, patterning, and remodeling.Angiogenesis. 2009; 12: 113-123
- Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?.Int J Dev Biol. 2011; 55: 563-567
- Remodelling the extracellular matrix in development and disease.Nat Rev Mol Cell Biol. 2014; 15: 786-801
- Morphomolecular motifs of pulmonary neoangiogenesis in interstitial lung diseases.Eur Respir J. 2020; 55: 1900933
- Endothelial MT1-MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis.EMBO Mol Med. 2020; 12: e10862
- Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis.Front Physiol. 2014; 5: 1-13
Article Info
Publication History
Published online: August 13, 2021
Accepted:
July 26,
2021
Footnotes
Supported by the Swedish state under the agreement between the Swedish government and the county councils, the Avtal om Läkarutbildning och Forskning (ALF) agreement (M.L., M.O.B., J.A.N., and S.B.), Jubileumsklinikens Cancerfond , Lions Cancerfond , Stiftelsen Tornspiran , Kungliga och Hvitfeldtska Stiftelsen , Stiftelsen Assar Gabrielssons Fond , Wilhelm och Martina Lundgrens Vetenskapsfond , Serena Ehrenströms Fond , Torsten och Sara Janssons Fond , and NIH National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK74398 (K.E.M.).
Disclosures: None declared.
Identification
Copyright
© 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
