Journal of Cancer Clinical Research

All submissions of the EM system will be redirected to Online Manuscript Submission System. Authors are requested to submit articles directly to Online Manuscript Submission System of respective journal.
Reach Us +1 (202) 780-3397

Short Communication - Journal of Cancer Clinical Research (2019) Volume 2, Issue 2

Development of the humanized anti-MIC-1 monoclonal antibody repressing tumor angiogenesis in colon and prostate cancer xenograft models

Hansoo Lee

Kangwon National University, South Korea

Visit for more related articles at Journal of Cancer Clinical Research


The macrophage inhibitory cytokine-1 (MIC-1) is a member of transforming growth factor beta (TGF-β) superfamily and its expression has been shown to associate with several human cancers including breast, colon, and prostate cancers. MIC-1 expression/secretion has also been found to be increased by the hypoxic conditions in many cancer cell lines. Through various angiogenic assays, we have found that MIC-1 promotes angiogenesis by stimulating endothelial cells via the PI3K/Akt and ERK signaling pathways. In a mouse melanoma model, tumors derived from high MIC-1-expressing cells displayed faster growth and higher blood vessel formation than ones from low MIC-1-expressing cells, implicating that MIC-1 contributes to tumor growth by promoting tumor angiogenesis. To create antibodies blocking genius angiogenic action of MIC-1, we have created mouse hybridoma clones and chose two clones that produce antibodies with high partiality to the human MIC-1. One of these two antibodies adequately blocked MIC-1 capacity of animating endothelial cells. Likewise, in a mouse melanoma model, intravenous organization of this enemy of MIC-1 counter acting agent hindered tumor development and angiogenesis.

Next, an antiMIC-1 acculturated counter acting agent articulation vector was built from the mouse clone by CDR joining, while at the same time holding murine structure deposits that impact the antigen-restricting action. The counter MIC-1 acculturated IgG delivered in the vector transfected CHO cells had the option to square MIC-1-initiated angiogenesis. Besides, this adapted enemy of MIC-1 immunizer was additionally fit for repressing tumor development and intratumor vein arrangement in colon and prostate malignancy xenograft models. Generally, the current examination proposes that enemy of MIC-1 acculturated monoclonal counter acting agent could be restoratively helpful for angiogenesis-
related sicknesses including malignancy. Angiogenesis is a physiological procedure where fresh blood vessels are framed from prior vessels. It happens during ordinary development and advancement, just as during wound recuperating. Under physiological conditions, angiogenesis is firmly controlled by the intricate and facilitated activities of master angiogenic and hostile to angiogenic factors as indicated by the spatiotemporal necessities of cells or tissues.

To date, many pro-angiogenic factors and their cognate receptors have been identified, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), angiopoietin (Ang), hepatocyte growth factor (HGF), and epidermal growth factor (EGF).Tumor angiogenesis is a hallmark of cancer and plays a crucial role in providing oxygen and nutrients to tumor cells during cancer progression and metastasis. Under pathological conditions, many pro-angiogenic factors and their receptors are upregulated; among these factors, VEGF is generally regarded as a key regulator of tumor angiogenesis. Bevacizumab, an enemy of VEGF immunizer, was as of late created as a disease treatment to stifle tumor angiogenesis. Although bevacizumab is clinically effective for treating patients with a variety of cancers, it has frequent complications due to its inhibition of VEGF signaling in normal endothelial cells, which express high levels of VEGF receptors (VEGFRs).Significantly, bevacizumab treatment is related with extreme reactions, including dying, proteinuria, hypertension, gastrointestinal puncturing, and stroke. Furthermore, in glioblastoma multiforme patients, bevacizumab treatment is associated with the presence of tumor cells that have an infiltrative phenotype, and high levels of matrix metalloproteinase (MMP)-2 and membrane-type 1 MMP. In addition, long-term bevacizumab treatment can lead to the development of drug resistance, due to the upregulation of other redundant tumor-derived angiogenic factors, including Ang, EGF, HGF, and PDGF. Despite the wide-scope of clinical helpfulness of bevacizumab for malignancy treatment, the distinguishing proof of novel angiogenic remedial targets and advancement of novel medications as option or mix medicines with existing medications are expected to improve the endurance and personal satisfaction of disease patients.

In the present article, we review the role and relevance of VEGF/VEGFR and four other therapeutic targets in tumorigenesis, as well as the current status and mechanisms of action of therapeutic antibodies being developed for anti-angiogenic therapy VEGF, first identified as a factor that promotes vascular permeability and vascular endothelial cell mitosis in the 1980s, is a key player in angiogenesis, as well as in endothelial proliferation, migration, and nitric oxide (NO) release. The mammalian VEGF proteins are dimeric glycoproteins with a molecular weight of approximately 40 kDa. Although VEGF-A is the most well characterized VEGF isoform, the VEGF family consists of five distinct isoforms: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF). Structurally, VEGF proteins have eight regularly spaced cysteine residues, which form intramolecular disulfide bonds that generate three loops; two intermolecular disulfide bonds allow for a homodimer structure between two VEGF molecules. In addition, VEGF has various alternative splice variants, which exhibit different binding affinity for VEGFR co-receptors, including neuropilins and heparin sulfate proteoglycans.

For instance, VEGF-A, VEGF-B, and PlGF can be divided into five (VEGF-A121, VEGF-A145, VEGF-A165, VEGF-A189, and VEGF-A206), two (VEGF-B167 and VEGF-B186), and four (PlGF-1, PlGF-2, PlGF-3, and PlGF-4) variants. Among the VEGF-A variations, VEGF-A165 and VEGF-A189 tie neuropilins and heparin sulfate proteoglycans, while VEGF-A121 doesn't tie either. Critically, this atomic assorted variety modifies bioavailability and action, which thusly, takes into consideration the commencement of different cell reactions.VEGF-mediated cellular functions occur via the activation of three receptors: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). VEGFRs are individuals from the receptor tyrosine kinase (RTK)
superfamily and are made out of an extracellular area with seven immunoglobulin (Ig)- like areas, a transmembrane space, a juxta layer space, and an intracellular space with a split tyrosine kinase space and C-terminal tail. Ig-like areas are engaged with ligand authoritative; specifically, Ig-like spaces 2 in VEGFR-1 and Ig-like areas 3 in VEGFR-2 are related with ligand-restricting site and ligand-restricting particularity, individually.

Upon ligand official, VEGFRs structure homo-and heterodimers, which prompt tyrosine transphosphorylation of the intracellular kinase areas and actuates signal transduction. VEGF signaling is one of the major signaling pathways required for embryonic vascular development and angiogenesis. VEGF-A, VEGF-B, and P1GF are constitutive VEGFR-1 agonists that induce migration and proliferation. In endothelial cell and macrophages, VEGFR-1 initiates migration by stimulating the phosphatidylinositol-4,5-bisphophate 3-kinase (PI3K)/Akt-Rac1 pathway through a receptor for activated protein kinase C 1. PI3K pathway activation by VEGFR-1 is also linked to endothelial cell proliferation and tubulogenesis. In addition, stimulation of monocyte VEGFR-1 induces migration through the activation of several intracellular signaling molecules, including PI3K, Akt, extracellular signal–regulated kinases (ERK)1/2, and p38 mitogen-activated protein kinase.

Get the App