Mast Cells (Part 2): Mast Cells And Cancer

This is a multi-part series on mast cells:

1. Mast Cells (Part 1): Stabilize Mast Cells And Remove Brain Fog

2. Mast Cells (Part 2): Mast Cells And Cancer

3. Mast Cells (Part 3): The Mast Cell-Glia Interaction In Chronic Inflammation

In this post we will discuss the angiogenic (growth supporting) factors of mast cells in cancer.

Mast cell degranulation (mast cells releasing chemical signals) serves a multiplex of functions (not an exclusive list): 

• Attracts inflammatory cells R

• Initiates immune response R

• Mediates tissue modeling/repair R

Mast cells have a variety of receptors which produces various effects (proangiogenic, anti-inflammatory, allergy response, etc). R R R R

They can either inhibit the growth of tumors of exacerbate their growth, so targeting mast cells can be a good cancer therapy alternative. R

Through the release of cytoplasmic granules and cytokines (mainly IL-1, TNF-α, IL-6) and growth factors (vascular endothelial growth factor, TGF-β, fibroblast growth factor-2, angiopoietin-1) mast cells are angiogenic (stimulating growth of tumors). R

There is an inverse correlation between IgE (allergic) response and cancer, as IgE (binding to Fc) can act as a tumor supressor. R R

Tumor-associated mast cells (TAMCs) are present in the microenvironment of several human solid and hematologic tumors. R R

Peritumoral and/or intratumoral mast cell density is increased in different types of human cancer. R

These TAMCs produce many growth factors including stem cell factor (SCF, acting on CD117/kit), vascular endothelial growth factors (VEGF, acting on VEGFR-1/2), fibroblast growth factor 2 (FGF-2), angiopoietin 1 (Ang1, acting on Tie2R), chemokine/interluekin 8 (Il-8, acting on CXCR1 and CXCR2) and nerve growth factor (NGF). R R R R R

These growth factors (as well as platelet-derived growth factor-β (PDGF-β), IL-6, IL-10, thymidine phosphorylase (TP), and chymase) are released and stimulate further growth. R R

Mast cells express CCR2, CXCR2, and CXCR3, which can bind to TAMC’s CCL2, CXCL1, and CXCL10 ligands. R R

PGE2 and histamine are chemotactic for mature mast cells (via EP2 receptor and H4R). R R

Leukotriene B4 (LTB4) is a leukotriene chemoattractant involved in inflammation and recruits mast cells via activation of BLT1 and BLT2. R

Osteopontin (OP, upregulated in  cancer) induces mast cell migration/degranulation. R R

Tryptase (high in cancer and mast cells) is a proangiogenic factor. R

Chymase remodels the extracellular matrix (ECM), induces angiogenesis by activating metalloproteinases (MMPs), such as MMP-9, which releases proangiogenic mediators. R

Pro Tumor Role Of Mast Cells in Human Cancer: R R

• Angioimmunoblastic T-cell lymphoma - Tryptase

• Bladder - Tryptase, Toluidine (blue)

• Brain - Trypatase, CPA3 R

• Breast - Trypatse R R

• Cholangiocarcinoma - Toluidine

• Colon - Toluidine blue/proteases, Alcian blue/toluidine blue, Chloroacetate esterase

• Colorectal - Giemsa, Toluidine, tryptase

• Cutaneous lymphoma - Tryptase, Toluidine

• Esophagus - Toluidine

• Follicular lymphoma - Tryptase

• Gastric - Toluidine, Chymase, Tryptase

• Hepatocellular - Tryptase

• Hodgkin’s lymphoma - Tryptase

• Lung - Tryptase, CD117

• Malignant pleural effusion - May-Gruenwald–Giemsa toluidine

• Melanoma - Gene expression/toluidine, Tyrptase

• Merkel cell carcinoma - Tryptase

• Pancreas - Tryptase, CD117

• Plasmacytoma - Toluidine, Tryptase

• Prostate - Tryptase

• Skin - Chloroacetate esterase/hematoxylin/toluidine blue

• Splenic marginal zone lymphoma - Tryptase

• Thyroid - Tryptase

• Waldenstrom’s macroglobulinemia - CD117/FcεRI/tryptase

Anti-Tumor Role Of Mast Cells in Human Cancer: R

• Breast cancer - CD117, Tryptase, Alcian blue/Giemsa

• Colorectal - Tryptase/chymase

• Diffuse large B-cell lymphoma - Tryptase

• Intestine - Chloroacetate esterase/chymase, Tryptase/CD117

• Lung - Tryptase/chymase

• Mesothelioma - Tryptase/chymase

• Melanoma - Tryptase/chymase

• Non-small-cell lung cancer - Tryptase/chymase

• Ovarian cancer - Tryptase

• Pancreas - CD117

• Prostate - CD117, Toluidine blue

• Skin - Tryptase/CD117, Giemsa

VEGFs can be chemotactic for mast cells. R

For example, VEGF-A165 is proangiogenic and VEGF-A165b is antiangiogenic. R

Human neutrophils, under certain circumstances, can produce both pro- and antiangiogenic isoforms of VEGF-A. R

Via production of IL-8, mast cells can make tumor cells chemotherapy drug resistant (via Epithelial-to-mesenchymal transition (EMT)). R R R

Mast cell density was not correlated with prognosis in superficially invasive melanomas, although low mast cell count in perilesional stroma of deeply invasive melanomas may predict poor survival. R

By suppling MMP9, mast cells were pro-tumorgenic in the initial stages of prostate cancer, but in later stages, was dispensable. R R

VEGF-B (produced by macrophages/mast cells), plays a role in early colon cancer development. R R

Dependent on where tryptase and chymase is released plays a role whether mast cells are protective in melanoma. R

Intratumoral mast cells inhibited tumor growth in prostate cancer, whereas peritumoral mast cells stimulated it. R

Inflammation (hypoxia, the accumulation of lactic acid/lactate, adenosine, PGE2, IFN-γ, and by low pH - all activate mast cells) creates recruitment (mast cells release SCF, VEGF, Ang1, Tie2). R R R R R R R

Hypoxia (ie increased HIF1a) on mast cells increases il-6 and VEGF-A. R R R

Adenosine (from mast cells and tumors, increased in cancer) is immunosupressive in potentiates mast cells to release histamine production of angiogenic factors from human mast cells and macrophages. R R R R R R R

COX2 -> PGE2 -> angiogenic and lymphangiogenic factors. R

CXCL1, CXCL10, and CXCL12 on mast cells -> IL-8 = angiogenesis/lymphangiogenesis via the recruitment of mast cells to the edge of solid tumors. R R

Back to IgE (without an antigen) induces VEGF-a angiogenesis from mast cells as seen in melanoma growth. R

Alarmins (upregulated in cancer cells) activate mast cells. R R

IL-33 (upregulated in SCC and skin cancers) induces the production of GM-CSF, CXCL8/IL-8, and VEGF-A from mast cells. R R R R

Antitumor IgG immune complexes may activate mast cells. R

OP (high in breast cancer) migrates/degranulates mast cells. R R

Platelet-Actvating Factor (PAF) from mast cells up regulates CXCR4 making them migrate to lymph nodes. R R

Estrogen receptor β (ERβ) antagonists may help with mast-cell promoted tumor growth. R

Killing mast cells (which can cause colon tumor cells to grow) with Fcε-PE40 chimeric toxin inhibits colon tumor development in vivo. R

Inhibition of mast cell degranulation by cromolyn inhibited Myc-induced pancreatic islet tumors experimental pancreatic and thyroid cancers, cholangiocarcinoma and prostate cancer (this one only in mice). R R R R R

Via modulation of p38/P53/p21 mast cells can promote chemotherapy and radiotherapy resistance. R

Blocking the CXCR4–CXCL12 pathway inhibits sunlight-induced skin cancer from mast cells. R

Notch-4 (via Int-3/ANK/IKK/P50) in breast cancer can either become pro- or anti- angiogenic, so inhibiting NF-kB (via GSK3β) may help, although could potentiate VEGF. R R R

Heparin (and HB-EGF) suppresses proliferation and reduces the number of breast cancer cell colonies (such as triple-neg breast cancer). R R R

Toll-like receptor agonists (specifically TLR2/4/6) can activate mast cells against tumor cells. R R R

MMP9 inhibition:

• Amentoflavone R

• Curcumin R R

• Goji Berries R

ER-beta inhibition:

• Melatonin R

• Milk Thistle R

Heparin (…can be taken by prescription, so why not?)

TLR agonism:

• Lectins (don’t use if lectin sensitive)

P53 normalization:

• Aronia R

• Chitosan R

• Resveratrol R

VEGF inhibition:

• Amentoflavone R

• Curcumin (decreases VEGF in cancer, increases VEGF in diabetes) R R R

• Green Tea (EGCG also inhibits integrins and MCP-1 resulting in lower migration and adhesion of mast cells/lower angiogenesis and recruitment of inflammatory cells) R R

Il-8 inhibition:

• Curcumin R

• Luteolin R R

• Quercetin R R R R R

Hif1a inhibition:

• Astragalus R

• Curcumin R

• Ginseng R

Fgf2 inhibition:

• Curcumin R

• Quercetin R

• Resveratrol R

Ang1 inhibition:

• Primrose Oil (and other GLAs) R

Osteopontin inhibition:

• Curcumin R

• Low Oxalate Intake (possibly) R

• Resveratrol R

Tyrosine kinase inhibition:

• Curcumin R

• Luteolin R

• Quercetin R

Tryptase inhibition:

• Astragalus R

• Luteolin R R

• Quercetin R R

GSK3β inhibition:

• Gleevec (Imatinib mesylate - script only) R

• Resveratrol R

• Other (drug) MC-Cancer Advanced Therapies R