How Mushrooms Inhibit VEGF and Tumor Blood Vessel Growth

Mushrooms & Cancer

40-60% tumor growth inhibition in xenograft mice

Lin et al. (2019, Cancers) found that cordycepin from Cordyceps militaris suppressed tumor blood vessel formation and reduced tumor growth by 40-60% in mouse models by blocking a signaling protein endothelial cells need to respond to VEGF.

Lin et al., Cancers, 2019

3 pathways

upstream VEGF secretion, receptor binding, and downstream FAK signaling

2005

year Ganoderma was shown to reduce VEGF secretion directly from prostate cancer cells

2022

year Antcin K from Antrodia was shown to block VEGFR2 phosphorylation and STAT3 signaling

Lin et al., Cancers, 2019

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Tumors need blood. A mass of cancer cells no larger than a few millimeters can survive by absorbing oxygen and nutrients from nearby tissue, but growth beyond that requires dedicated blood vessels. VEGF, a signaling protein whose full name is vascular endothelial growth factor, is how most tumors recruit those vessels: the tumor secretes VEGF, nearby endothelial cells (the cells that form blood vessel walls) detect it, and they begin dividing, migrating, and forming new capillary networks.

Blocking this process is one of the established strategies in cancer treatment. How mushroom compounds inhibit VEGF and tumor blood vessel growth turns out to involve three mechanistically distinct intervention points, identified in studies from 2004 to 2022. Each targets a different stage of the VEGF signaling cascade, and they work through different molecular routes. For the broader picture of medicinal mushrooms in cancer treatment, see medicinal mushrooms in cancer treatment: a complete guide.

What VEGF Does and Why Three Intervention Points Matter

VEGF is not a single molecule but a family of related signaling proteins. VEGF-A is the primary tumor angiogenesis driver. When a tumor secretes VEGF-A, it binds to a receptor called VEGFR2 (also called KDR or flk-1) on the surface of nearby endothelial cells. VEGFR2 is the docking port: when VEGF attaches, it activates the receptor by triggering a chemical change called phosphorylation. That activated receptor then passes the signal inward through a series of relay proteins, ultimately telling the endothelial cell to divide, migrate toward the tumor, and form a new vessel.

Three intervention points exist in this chain. The first is before VEGF leaves the tumor cell: if you can prevent the tumor from producing or secreting VEGF, the signal never reaches endothelial cells. The second is at the receptor itself: if you can block VEGF from binding to VEGFR2, the signal cannot start. The third is downstream of the receptor: if you can disrupt the relay proteins inside the endothelial cell, the signal cannot complete even if VEGF binds successfully.

Pharmaceutical anti-angiogenics like bevacizumab (Avastin) and sunitinib target primarily the first two points: bevacizumab captures circulating VEGF before it reaches endothelial cells, and sunitinib blocks VEGFR2 phosphorylation. The mushroom research documents mechanisms at all three points, including a downstream endothelial disruption mechanism (FAK/p53) that pharmaceutical anti-angiogenics do not target.

Mechanism 1: Stopping VEGF Before It Leaves the Tumor Cell

The upstream mechanism was documented for Ganoderma lucidum in 2005 by Stanley and colleagues.^[1] They exposed human prostate cancer cells to Ganoderma extract: both androgen-sensitive LNCaP cells and androgen-insensitive PC-3 cells. Both cell lines secreted less VEGF and less TGF-beta1 (a related growth factor that also promotes angiogenesis) in response to the extract.

The implication is significant: the Ganoderma compounds were not acting on endothelial cells at all. They were acting on the tumor cells, reducing how much VEGF those cells produced in the first place. If the tumor does not secrete the signal, the endothelial cells never receive the instruction to grow.

This upstream suppression mechanism has advantages over receptor-level blocking. VEGF acts not only on VEGFR2 but also on other receptors and in autocrine signaling loops (where the tumor cell also responds to its own VEGF). Suppressing VEGF secretion cuts off all of these loops simultaneously.

A 2004 animal study using Ganoderma polysaccharide peptide (GLPP) confirmed antitumor and anti-angiogenic activity in tumor-bearing mice, showing that the polysaccharide-peptide complex reduced both tumor weight and new vessel formation in vivo.^[9] This confirmed that upstream suppression translated to measurable anti-angiogenic effects in a living organism, not just in cell culture.

Mechanism 2: Blocking VEGF from Docking at Its Receptor

The receptor-level mechanism was identified for Antrodia cinnamomea, a medicinal mushroom from Taiwan with one of the most extensively studied anti-angiogenic compound profiles.

Cheng and colleagues showed in 2005 that polysaccharides from Antrodia cinnamomea blocked VEGF binding to its KDR/flk-1 receptor on endothelial cells and inhibited the VEGF-induced cell migration and tube formation that normally follow that binding.^[2] To understand the mechanism: the Antrodia polysaccharides physically occupied the docking site on VEGFR2 that VEGF normally attaches to. With the receptor occupied, VEGF could not bind; without binding, VEGFR2 could not be activated; without activation, the downstream signaling cascade could not start.

Yang and colleagues extended this finding in 2009, examining how molecular weight affects potency among Antrodia polysaccharides.^[3] High-molecular-weight polysaccharide fractions showed the strongest inhibition of VEGF-induced endothelial proliferation and tube formation. The mechanism included suppression of cyclin D1, a protein that controls when cells begin dividing, providing an additional barrier to new vessel formation beyond the initial receptor competition.

Achudhan and colleagues provided a more precise picture of receptor-level targeting in 2022, testing Antcin K, a lanostane triterpenoid from Antrodia cinnamomea, in a model of VEGF-dependent angiogenesis in rheumatoid arthritis synovial tissue.^[4] Antcin K specifically blocked the phosphorylation of VEGFR2, the chemical activation step that must occur before the receptor can pass its signal inward. Downstream of VEGFR2, Antcin K also suppressed STAT3 (a protein that carries the signal from the receptor to the cell nucleus and activates angiogenic genes). This study is the most molecularly specific characterization of receptor-level targeting by any mushroom compound published to 2022.

For the cancer-specific research on Antrodia cinnamomea compounds, see how Antrodia induces cancer cell death.

Mechanism 3: Disrupting the Endothelial Cell Machinery Downstream

The third mechanism is the most recently discovered and the most mechanistically distinct from the pharmaceutical approaches. It was documented for cordycepin, an adenosine analog produced by Cordyceps militaris, in a 2019 study by Lin and colleagues published in Cancers.^[5]

Cordycepin's target is FAK, which stands for focal adhesion kinase. FAK is a protein that sits at points where endothelial cells attach to their surrounding tissue matrix. For an endothelial cell to respond to VEGF by migrating toward a tumor and forming a new vessel, FAK must be active: it provides the cell with both the mechanical ability to move and the survival signals it needs during that migration. Without active FAK, endothelial cells cannot effectively respond to VEGF even if VEGF is present and its receptor is activated.

Lin's study showed that cordycepin dose-dependently suppressed three endothelial processes that depend on FAK: cell proliferation, cell migration, and tube formation (the formation of hollow capillary-like structures, the final step of angiogenesis). The mechanism was FAK dephosphorylation (turning FAK off) combined with upregulation of p53 (a tumor suppressor protein that pushes cells toward death rather than growth). In xenograft mouse models, where human cancer cells were implanted in mice, cordycepin reduced tumor growth by 40-60%.

The significance of this mechanism is that it is downstream of VEGFR2. Even if VEGF successfully binds its receptor and activates the downstream signaling cascade, the endothelial cell cannot act on those signals without functional FAK. Cordycepin's effect at FAK therefore represents an intervention point that is independent of whether VEGF is present and whether its receptor is blocked.

For more on cordycepin and its mechanisms across cancer and performance research, see ganoderic acids and cancer: specific anti-tumor research.

One Compound Complex That Hits Multiple Points: Phellinus linteus

Several mushroom compounds appear to operate at more than one point in the pathway simultaneously. The most documented multi-mechanism example is a protein-bound polysaccharide from Phellinus linteus, the mushroom also known as Sang-hwang or black hoof mushroom.

Sliva and colleagues documented in 2008 that Phellinus linteus extract inhibited breast cancer cell growth, reduced VEGF secretion from those cells, and blocked endothelial tube formation in parallel, through inhibition of AKT phosphorylation.^[7] AKT (also called PKB) is a central survival and growth-signaling hub inside cells, activated both by VEGF signaling and by other growth inputs. By blocking AKT, Phellinus linteus compounds reduced both tumor cell VEGF production and endothelial cell ability to respond to it.

Song and colleagues demonstrated in 2011 that a specific protein-bound polysaccharide (PBP) isolated from Phellinus linteus simultaneously inhibited colon cancer proliferation, reduced VEGF and MMP (a matrix-degrading enzyme involved in invasion) expression, and suppressed invasion in SW480 colorectal cancer cells.^[6] The study also identified interference with Wnt/beta-catenin signaling, a pathway that controls cell growth and survival across many cancer types. A single polysaccharide-protein complex acting simultaneously on tumor growth, invasion, and angiogenesis through at least two pathways represents the broadest documented multi-mechanism activity of any compound in this cluster.

Anti-Angiogenic Activity Across Multiple Species and Compound Classes

The three mechanisms described above have been replicated across different mushroom species and different compound classes, suggesting this is not a property unique to one or two specialist species.

Chen and colleagues demonstrated in 2005 that high-molecular-weight polysaccharide fractions isolated from multiple different medicinal fungi all showed anti-angiogenic activity in HUVEC-based tube formation assays (HUVEC being the standard human endothelial cell line used for angiogenesis testing).^[8] The anti-angiogenic activity was common to polysaccharides from different species, confirming that high-molecular-weight fungal polysaccharides represent a broad class of anti-angiogenic compounds rather than species-specific exceptions.

The compound diversity extends beyond polysaccharides. The mechanisms identified across the studies in this article span lanostane triterpenoids (Antcin K), adenosine analogs (cordycepin), polysaccharide-protein complexes (Phellinus PBP), polysaccharide peptides (Ganoderma GLPP), and polysaccharides (Antrodia fractions), suggesting that anti-angiogenic activity has evolved or been retained across functionally very different compound classes.

For how this fits within the broader evidence on mushrooms and cancer prevention, see daily mushroom consumption and cancer risk reduction and beta-glucans and anti-tumor immunity: mechanisms explained. For which mushroom species show the strongest documented anti-angiogenic effects across the literature, see anti-angiogenic mushrooms: which species show the strongest effects?.

The Bottom Line

Research from 2004 to 2022 identified three mechanistically distinct intervention points where mushroom compounds disrupt VEGF-driven tumor angiogenesis. Ganoderma compounds reduce VEGF secretion upstream in tumor cells before the signal reaches endothelial cells. Antrodia polysaccharides and Antcin K block VEGF at the receptor level, competing for binding sites and blocking VEGFR2 phosphorylation. Cordycepin targets downstream of the receptor by deactivating FAK and upregulating p53 in endothelial cells, producing 40-60% tumor growth inhibition in mouse xenograft models. Phellinus linteus protein-bound polysaccharide demonstrates multi-point activity, simultaneously reducing VEGF secretion, blocking AKT, and suppressing invasion. All of this evidence is preclinical; no clinical trial has specifically tested a mushroom compound's anti-angiogenic effect in human cancer patients.

Frequently Asked Questions

How do mushrooms lower VEGF levels?

Mushroom compounds lower VEGF through two documented mechanisms. Ganoderma lucidum extract reduced the amount of VEGF secreted by prostate cancer cells in a 2005 study, working at the tumor cell level before the signal ever reaches blood vessel cells. Separately, polysaccharides from Antrodia cinnamomea blocked VEGF from binding to its receptor on endothelial cells, preventing the signal from triggering new vessel growth. Both effects are from preclinical cell and animal studies; no clinical trial has measured VEGF changes from mushroom supplementation in cancer patients.

What compound in mushrooms blocks VEGF?

Multiple compounds have been identified. Ganoderma polysaccharide peptide (GLPP) suppresses VEGF secretion from tumor cells. Antrodia cinnamomea polysaccharides compete with VEGF for binding to its surface receptor (KDR/VEGFR2). Antcin K, a triterpenoid from Antrodia, blocks VEGFR2 phosphorylation and downstream STAT3 signaling. Cordycepin from Cordyceps militaris works downstream of the receptor, deactivating FAK in endothelial cells. The compound-to-mechanism relationship varies by mushroom species.

How does VEGF help tumors grow blood vessels?

Tumors secrete VEGF (vascular endothelial growth factor), which travels to nearby blood vessel cells and binds to a surface receptor called VEGFR2. That binding activates VEGFR2 through a chemical modification (phosphorylation), which then passes a signal inward through relay proteins like STAT3, ultimately instructing the cell to divide, migrate toward the tumor, and form a new capillary. Without this process, tumors cannot grow beyond a few millimeters.

What naturally blocks VEGF signaling?

Compounds documented to block VEGF signaling at different points include: Antrodia polysaccharides (compete with VEGF for receptor binding), Antcin K triterpenoid (blocks VEGFR2 phosphorylation and STAT3), Ganoderma polysaccharide peptide (suppresses VEGF secretion from tumor cells), and cordycepin (deactivates FAK, a protein endothelial cells need to respond to VEGF downstream of receptor activation). All of these findings are from preclinical laboratory studies.

Which mushroom compound targets the VEGF receptor?

Two compounds from Antrodia cinnamomea have documented receptor-level activity. High-molecular-weight polysaccharides physically competed with VEGF for binding to the KDR/flk-1 receptor, blocking VEGF from docking. Antcin K, a lanostane triterpenoid from the same mushroom, blocked VEGFR2 phosphorylation (the activation step) and downstream STAT3 signaling. Both were confirmed in human endothelial cell studies.

Sources & References

1. 1RTHM-00087·Stanley, Gwenaelle et al. (2005). “Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-beta1 from prostate cancer cells..” Biochemical and biophysical research communications.Study breakdown →PubMed →↩
2. 2RTHM-00150·Cheng, Jing-Jy et al. (2005). “Study for anti-angiogenic activities of polysaccharides isolated from Antrodia cinnamomea in endothelial cells..” Life sciences.Study breakdown →PubMed →↩
3. 3RTHM-00321·Yang, Chih-Min et al. (2009). “Anti-angiogenic effects and mechanisms of polysaccharides from Antrodia cinnamomea with different molecular weights..” Journal of ethnopharmacology.Study breakdown →PubMed →↩
4. 4RTHM-00739·Achudhan, David et al. (2022). “Antcin K inhibits VEGF-dependent angiogenesis in human rheumatoid arthritis synovial fibroblasts..” Journal of food biochemistry.Study breakdown →PubMed →↩
5. 5RTHM-00573·Lin, Yi-Ting et al. (2019). “Cordycepin Suppresses Endothelial Cell Proliferation, Migration, Angiogenesis, and Tumor Growth by Regulating Focal Adhesion Kinase and p53..” Cancers.Study breakdown →PubMed →↩
6. 6RTHM-00437·Song, Kyoung-Sub et al. (2011). “Protein-bound polysaccharide from Phellinus linteus inhibits tumor growth, invasion, and angiogenesis and alters Wnt/β-catenin in SW480 human colon cancer cells..” BMC cancer.Study breakdown →PubMed →↩
7. 7RTHM-00271·Sliva, D et al. (2008). “Phellinus linteus Extract in Breast-Cancer Cell Models: What This 2008 Study Actually Found.” British journal of cancer.Study breakdown →PubMed →↩
8. 8RTHM-00148·Chen, Shih Chung et al. (2005). “Antiangiogenic activities of polysaccharides isolated from medicinal fungi..” FEMS microbiology letters.Study breakdown →PubMed →↩
9. 9RTHM-00067·Cao, Qi-Zhen et al. (2004). “Antitumor and anti-angiogenic activity of Ganoderma lucidum polysaccharides peptide..” Acta pharmacologica Sinica.Study breakdown →PubMed →↩