Macrophage polarization by HRG and its effects on Tumor
Macrophagerepolarization and itseffects on TumorTO TAME AN ORGAN
Tumors and Cancer Tumor or neoplasm is a vesicular bulging in particular tissuesdue to uncontrolled cell proliferation. While cancer is bydefinition malignant, a tumor can be benign, pre-malignant, ormalignant, or can represent a lesion without any cancerouspotential whatsoever. Benign tumors do not invade other tissues. They are rarely athreat to life unless they compress vital structures or aresecreting harmful chemicals in the bloodstream. Malignant tumors can invade other organs, spread to distantlocations (metastasis) and become life-threatening.
The problem :1 The growth of blood vessel network in newly formed tissuesfrom already existing vessels is called angiogenesis. Thisprocess is promoted by expression of VEGF. VEGF expression is promoted by hypoxia and β-catenin. PKG downregulates β-catenin. In its absence there is anincessant expression of VEGF causing formation ofirregularly shaped, hyper-permeable blood vessels whichslowly thicken due to accumulation of debris and plasma.This keeps tumor in a constant state of hypoxia.
The misconception The discovery of VEGF led to the belief that by blocking theaction of this protein , the supply of food and oxygen to thetumor can be cut which will make the tumor starve and therebyeliminate it. A drug named “avastin” was developed which was able to blockthe functions of VEGF. This was considered the “silver bullet”treatment. But this was not successful as anti-angiogenic ‘‘vessel pruning’’strategies like this can worsen this situation by aggravatinghypoxia.
The Problem : 2 Tumor blood vessels have perivascular detachment, vesseldilation, and irregular shape. They are not smooth like normaltissues, and are not ordered sufficiently to give oxygen to all ofthe tissues. Also , abnormal vasculature in tumor cells impedes the deliveryof chemo/immuno-therapeutic agents. This causes a state ofhypoxia which initiates a series of enzyme activity and increasesmetastasis. This also prevents the proper delivery of chemotherapeuticagents thus protecting the tumor.
The inconsistency In non-progressing or regressing tumors, TAMs are biased toa classic macrophage activation,M1-likeprogram, characterized by pro-inflammatory activity In malignant tumors, TAMs resemble alternatively activatedmacrophages (M2-type), that increase angiogenesis andtumor cell intra/ extravasation and growth; they suppressantitumor immunity by preventing activation of dendriticcells, cytotoxic T lymphocytes, and natural killer cells.
The Solution The need to normalize the tumor vessels was felt (R. K.Jain, 2005) which attracted attention to abnormalities invascular endothelial cells and pericytes. (which was marked tobe the presence of RG5 by Hamzah et al, 2008) Rolny et al suggested that targeting abnormal polarization ofTAMs can normalize tumor vessels. TAMs usually exhibit M2 like phenotype and secrete cytokineslike IL-10, CCL-17,CCL-22 and proangiogenic factors like VEGFand PIGF.
HRG TAMs consist of distinct subsets, which coexist intumors, adapt to the changingmicroenvironment, and can be re-educated byimmunoregulatory cues. This has primed interest in developingtherapies, aimed at skewing TAMs to an M1-likephenotype. Nonetheless, only few molecules havebeen identified to orchestrate this process so far. HRG (histidine-rich glycoprotein) is one of them.
HRG HRG is a multidomain plasma protein synthesized byhepatocytes and has important function in regulation oftumor angiogenesis and immunity. The increase of oxygenation in HRG+ tumors caused byvascular normalization seems to provide a stimulus forpolarizing TAMs away from M2-like type, which couldfurther sustain the normalized vasculature.
HRG- TAM interaction Exposure of TAMs to HRG downregulated the M2 markers suchas MRC1, Arg1, IL10, and CCL-22 and simultaneously elevated M1markers such as IL6 and CXCL-9. Accordingly, tumor-infiltratedCD8+ T cells, natural killer (NK) cells, and dendritic cells (DCs)increased and their functions improved in HRG+ tumors Thus we are able to increase immune surveillance in the tumorand control its growth without aggravating hypoxia i.e. withoutincreasing metastasis. The repolarization of TAMs increases the vessel normalizationwhich gives an additional edge over anti-angiogenic agentsalone.
How does HRG skew TAMs awayfromM2-like phenotype? HRG serves as an antagonist to Fcγ receptors which areexpressed in macrophages. Stromal accumulation of autoantibodies in premalignantskin, through their interaction with activating FcγRs, regulaterecruitment, composition, and bioeffector functions ofleukocytes in neoplastic tissue, which in turn promote neoplasticprogression and subsequent carcinoma development. (andreu etal ,2010) Thus blocking fcγR skew TAMs towards M1-like configuration.
HRG reduces PIGF HRG reduced PlGF production by TAMs by downregulating it’sgene. The deletion of PlGF in macrophages phenocopied antitumor andvascular normalization effects of HRG treatment. HRG did not further suppress tumor growth in the absence ofhost-derived PlGF. Similar observations were made whenanalyzing metastasis. PlGF deficiency altered tumor immunity. However, HRGoverexpression did not further affect the infiltration of these cellsin PlGF deficient mice
HRG decreased themetastatic index(nodules per gramtumor) The reduced tumorspread was partlyindependent of tumorgrowth inhibition. PHH3 staining showsproliferating tumor cells.Slow growth in HRG+ tumors
HRG allows more dendriticcells, Natural killer cellsand cytotoxic Tlymphocytes in the tumor. It increases production offactors that repolarize M2-macrophages into M1-macrophages. It alsoincreases the TAM density.
*Doxorubicin intercalates the DNA andblocks polymerase activity. It is generallyused in chemotherapy. Increased expression ofHRG increases impact ofinflammation andchemotherapy ,decreasesmetastasis and regulatesangiogenesis. It skews TAMs to allow aninflammatory response.The Impact
Referenceso “HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization andVessel Normalization through Downregulation of PlGF” by Rolny et al (2011)o “Macrophage Diversity Enhances Tumor Progression and Metastasis” by Qian and Pollard(2010)o “Polarization of Tumor-Associated Macrophages: A Novel Strategy for VascularNormalization and Antitumor Immunity” by Huang, Snuderl and Jain (2011)