Anti-angiogenesis approaches in medicine -
Blocking these cytokines with neutralizing antibodies reduced tumor vascularization and improved sensitivity to bevacizumab Tripathi et al. Liu et al. Obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors in murine breast cancer model Incio et al.
Inhibition of IL-6 normalized tumor vasculature, reduced hypoxia, and restored sensitivity to anti-VEGF therapy. Heterogeneous pericyte coverage has been described in several types of tumors, at different stages of tumor progression, and even within a single tumor stage Hida et al.
The reduction in tumor vascularity induced by anti-VEGF therapy enhances the recruitment of pericytes to maintain blood vessel function and integrity Bergers and Hanahan, Increased pericyte coverage of these blood vessels supports tumor endothelium to survive and function despite the anti-angiogenic drug Bergers and Hanahan, ; Lord and Harris, In addition, pericytes can release pro-angiogenic factors in response to PDGF Lord and Harris, In the breast cancer vasculature, heterogenous pericyte coverage was identified Kim et al.
However, the impact of pericyte on resistance to anti-VEGF therapy in breast tumors is largely unknown. Vasculogenic mimicry and vessel co-option may decrease the dependence on classical angiogenesis by tumors Schneider and Miller, ; Bergers and Hanahan, ; Carmeliet and Jain, These alternative mechanisms render tumors insensitive to anti-angiogenic agents by allowing tumors to obtain the necessary blood supply when classical angiogenesis is limited Schneider and Miller, ; Haibe et al.
Vasculogenic mimicry is associated with aggressive breast cancer phenotypes and poor prognosis Shen et al. Bevacizumab failed to inhibit vasculogenic mimicry in the HCC breast cancer cell line Dey et al.
Besides, Sun et al. showed that the administration of sunitinib induced vasculogenic mimicry in animal models of TNBC which ultimately promoted resistance to sunitinib therapy Sun et al. Vascular co-option is another mechanism to escape angiogenesis inhibitors and has been shown to drive brain metastasis of breast cancer cells Ramadan et al.
Growing evidence supports the concept of the heterogeneity of the endothelium of vessels involved in angiogenesis Hida et al. Hida et al. showed that tumor blood vessels are heterogeneous and that tumor-associated endothelial cells had relatively large, heterogeneous nuclei, cell aneuploidy, and chromosomal alterations indicative of cytogenetic abnormalities Hida et al.
Altered gene and protein expression profiles in tumor endothelium have also been reported Aird, The heterogeneity of tumor endothelial cells may differ by tumor type, tumor microenvironment, and the stage of tumor growth Hida et al.
Grange et al. showed that breast cancer-derived endothelial cells did not undergo normal cell senescence in culture, had increased motility, and constantly expressed markers of endothelial activation and angiogenesis Grange et al.
These endothelial cells were resistant to the cytotoxic activity of chemotherapeutic drugs as compared to normal micro-endothelial cells Grange et al. The functional abnormalities of tumor-associated endothelial cells and the microvascular heterogeneity could explain, at least in part, the reduced efficacy of anti-angiogenic therapy in breast cancer by enabling endothelial cells an increased pro-angiogenic activity to acquire drug resistance Grange et al.
Lack of response to angiogenesis inhibitors may be explained in terms of the stage of progression, treatment history, and genomic constitution that exist in the tumor microenvironment Bergers and Hanahan, An analysis of human breast cancer biopsies demonstrated a plethora of pro-angiogenic factors in late-stage breast cancers including FGF-2, in contrast to earlier-stage tumors which preferentially expressed VEGF Relf et al.
Thus, resistance to anti-VEGF drugs in advanced-stage breast cancer may be explained by the dominance of FGF-2 and other pro-angiogenic factors in such stage of the disease Bergers and Hanahan, Invasive cancers commonly express multiple angiogenic factors and this heterogeneity occurs at an early point in time.
Genetic instabilities in the tumor cells may cause alterations of both the amount and type of pro-angiogenic factors expressed in a tumor which could further promote resistance to anti-angiogenic treatments Schneider and Miller, Cancer stem cells are a subpopulation of cancer cells capable of self-renewal, differentiation, and induction of tumorigenesis, metastasis, and drug resistance Li et al.
The potential of cancer stem cell trans-differentiating into endothelial cells has been reported in a variety of solid tumors Li et al. Bussolati et al. showed that breast cancer stem cells were able to differentiate into the endothelial lineage in the presence of VEGF Bussolati et al.
The stem cells acquired several endothelial markers and organized into capillary-like structures forming vessels in a xenograft animal model Bussolati et al.
Similarly, Wang et al. showed that breast cancer stem cells may trans-differentiate into endothelial cells that can form capillary-like vascular structures in the cell culture system and participate in tumor angiogenesis Wang et al.
An earlier study demonstrated that microRNAa miRNAa expression promoted tumor angiogenesis and metastasis in vivo by mediating endothelial trans-differentiation of breast cancer stem-like cells Tang et al.
Brossa et al. reported the ability of breast cancer stem cells to trans-differentiate to endothelial cells expressing endothelial markers under hypoxic conditions in vitro Brossa et al.
Notably, treatment with the VEGFR inhibitor sunitinib but not the VEGF inhibitor bevacizumab impaired the endothelial differentiation ability of breast cancer stem cells both in vitro and in vivo. Mechanistically, sunitinib, but not bevacizumab, suppressed HIF-1α required for endothelial differentiation under hypoxic conditions Brossa et al.
Together, increasing evidence suggests that cancer stem cell endothelial trans-differentiation supports tumor vascularization and partly contributes to the failure of anti-angiogenic drugs. The lack of efficacy of the conventional angiogenesis inhibitors necessitates exploring novel angiogenic pathways in breast cancer.
Given the heterogeneity of breast cancer and the complexity of angiogenesis, it is unlikely that the identification of a single target such as VEGF would be adequate in the treatment of this disease.
Interleukins ILs are a family of cytokines known to play essential roles in the regulation of several immune cell functions such as differentiation, activation, proliferation, migration, and adhesion Turner et al.
Interactions of ILs and their receptors in endothelial cells have been shown to regulate angiogenesis through pro-angiogenic and anti-angiogenic activity Ribatti, Serum IL-6 levels were elevated in breast cancer patients compared to controls Barron et al. Additionally, serum IL-6 and VEGF correlated positively in breast cancer patients Raghunathachar Sahana et al.
Higher expression of IL-6R was demonstrated in clinical specimens for patients with high-grade invasive ductal carcinoma Bharti et al.
A recent study by Hegde et al. showed that a crosstalk between IL-6 and VEGFR-2 signaling pathways exists in myoepithelial and endothelial cells isolated from clinical human breast tumors Hegde et al.
IL-6 epigenetically regulated VEGFR-2 expression through induction of proteasomal degradation of DNA methyltransferase 1 leading to promoter hypomethylation and angiogenic activity Hegde et al.
IL-8 is a pro-inflammatory cytokine that exerts its biologic activity through binding to its CXCR1 and CXCR2 receptors Waugh and Wilson, IL-8 enhanced the proliferation of cancer cells and produced a pro-angiogenic activity Waugh and Wilson, Serum IL-8 levels were significantly higher in breast cancer patients compared with healthy subjects and were associated with advanced disease Benoy et al.
High levels of IL-8 are secreted by stromal cells into the microenvironment of breast cancer patients compared to controls Razmkhah et al. Evidence from preclinical studies showed that IL-8 mediated invasion and angiogenesis of breast cancer cells Lin et al.
Cancer-associated adipocytes express high levels of IL-8 in breast cancer stroma thus promoting the pro-angiogenic effects of breast adipocytes Al-Khalaf et al.
In this context, ILexpressing adipocytes increased vascularity of tumor xenografts as indicated by increased expression of CD34, an endothelial cell marker Al-Khalaf et al. Neutralization of IL-8 or inhibiting its target receptors had been shown to reduce breast cancer growth and angiogenesis Lin et al.
Nannuru et al. showed that silencing of CXCR2 expression reduced tumor vascularity and inhibited spontaneous lung metastasis in an orthotopic animal model of breast cancer Nannuru et al.
Further, CXCR1 blockade with the small molecule inhibitor, repertaxin reduced metastasis in an animal model of breast cancer Ginestier et al. The platelet-derived growth factor PDGF family consists of four gene products PDGF-A, -B, -C, and -D that are combined into five different isoforms: PDGF-AA, -BB, -CC, -DD, and -AB Bartoschek and Pietras, These factors bind and activate their respective RTKs, PDGFR-α, and PDGFR-β.
PDGF family plays a key role in a wide range of oncologic activities essential for cancer growth including angiogenesis, fibrosis, and cellular migration Bartoschek and Pietras, High expression of PDGFs was correlated with an advanced presentation, increased recurrence, and poor survival in patients with invasive breast cancer Jansson et al.
PDGF is an important regulator for the motility of vascular smooth muscle cells induced by breast cancer cells Banerjee et al. Besides, the expression of HIF-1α in invasive breast cancer was significantly associated with angiogenesis and expression of PDGF-BB Bos et al. Earlier evidence showed that PDGFRs are expressed by breast cancer cells and endothelial cells in metastatic bone lesions in animal models Lev et al.
Imatinib remarkably inhibited PDGFR activation in breast cancer cells and tumor-associated endothelial cells and reduced microvessel density in the tumors Lev et al. Recently, Wang et al. provided evidence from cell culture and animal studies that the downregulation of PDGF-B greatly contributed to the metformin-induced vessel normalization in breast cancer Wang et al.
Fibroblast growth factors FGFs belong to a large family of growth factors that includes 23 members Hui et al. FGFs are key regulators of numerous physiological processes such as angiogenesis, wound healing, and embryonic development.
These functions are mediated by the binding of FGFs with their receptors FGFRs , which belong to the RTK family Hui et al. Growing evidence signifies the oncogenic impact of FGFs and FGFRs to promote cancer development and progression by mediating cancer cell proliferation, survival, epithelial-to-mesenchymal transition, invasion, and angiogenesis Wesche et al.
Chen et al. showed that dipalmitoylphosphatidic acid, a bioactive phospholipid, induced anti-angiogenic activity, and inhibited tumor growth in an experimental xenograft model of breast cancer Chen J.
These effects were attributed to transcriptional inhibition of FGF-1 expression leading to the downregulation of HGF Chen J. In the same context, Cai et al. showed that neutralizing FGF-2 by a disulfide-stabilized diabody inhibited tumor growth and angiogenesis in a mouse model of breast cancer Cai et al.
The antitumor activity was associated with a significant decrease in microvessel density and the number of lymphatic vessels Cai et al. Formononetin, an FGFR-2 inhibitor, demonstrated anti-angiogenic activity in breast cancer in both ex vivo and in vivo angiogenesis assays Wu et al.
Besides, formononetin significantly inhibited angiogenesis in vivo by reducing microvessel density and phosphorylated FGFR-2 levels in tumor tissue Wu et al. Recent evidence showed that FGFpositive tumors are resistant to clinically available drugs targeting VEGF and PDGF Hosaka et al.
The resistance is mediated by the ability of FGF-2 to recruit pericytes onto tumor microvessels through a PDGFR-β-dependent mechanism in breast cancer and fibrosarcoma models.
Dual targeting of the VEGF and PDGF produced a superior antitumor effect in FGFpositive breast cancer Hosaka et al. Angiopoietins Angs represent an imperative family of vascular growth factors that produce their biological effects through binding to the RTKs, Tie-1, and Tie-2 Akwii et al.
Angiopoietin-1 Ang-1 and angiopoietin-2 Ang-2 are best characterized for their role in angiogenesis and vascular stability Akwii et al. Ang-1 regulates the organization and maturation of newly formed blood vessels and promotes quiescence and structural integrity of vasculature Brindle et al.
Alternatively, Ang-2 antagonizes the effects of Ang-1 resulting in vessel destabilization Brindle et al. Ramanthan et al. indicated that high Ang-2 gene expression in breast cancer patients was associated with reduced survival Ramanathan et al.
In addition, a strong correlation existed between Angs and VEGF genes in breast cancer tissues Ramanathan et al. Besides, serum levels of Ang-2 were significantly higher in breast cancer patients compared to healthy control subjects. High Ang-2 serum levels had shorter survival than that of the low Ang-2 expression group Li et al.
Evidence from preclinical models also demonstrated that Ang-2 mediated initial steps of breast cancer metastasis to the brain Avraham et al. He et al.
showed that targeting Ang-2 with miRNAp reduced tumor growth, angiogenesis, and metastasis in animal models He et al. Besides, Wu et al. showed that oral administration of methylseleninic acid reduced microvessel density and increased pericytes coverage by inhibiting Ang-2 in a breast cancer animal model Wu et al.
Dual inhibition of VEGF-A and Ang-2 using a bispecific antibody promoted vascular regression and normalization in a model of metastatic breast cancer Schmittnaegel et al. Dual inhibition of Ang-1 and TGF-βR2 was also shown to suppress tumor angiogenesis in breast cancer in vivo Flores-Perez et al.
Notch receptors belong to a highly conserved signaling pathway that relies on cell-cell contacts to mediate a response to environmental signals in multicellular animals Aster et al.
Four different Notch receptors are expressed in humans, each is encoded by a different gene. In addition, four functional Notch ligands exist and belong to two families: members of the Delta family of ligands; Dll-1 and Dll-4, and members of the Serrate family of ligands; Jag-1 and Jag-2 Aster et al.
In breast cancer, Notch signaling promotes cell proliferation, self-renewal, anti-apoptotic effects, and angiogenesis Aster et al. Notch expression has been associated with the progression and recurrence of breast cancer Mollen et al. Proia et al. showed that blocking Notch-1 function with a specific antibody inhibited functional angiogenesis and breast cancer growth in animal models Proia et al.
HGF is a member of the plasminogen-related growth factor group and is a known angiogenic factor Nakamura and Mizuno, It is primarily expressed and produced by stromal cells, such as fibroblasts in mammary tissues Jiang et al. The angiogenic actions of HGF are mediated by binding to its RTK, MET on endothelial cells Organ and Tsao, ; Zhang et al.
In the activated endothelial cells, MET is upregulated thus modulating cell dissociation, motility, proliferation, and invasion Peruzzi and Bottaro, HGF regulates VEGF expression in tumor cells promoting angiogenic activity Matsumura et al.
Earlier studies showed that targeting HGF with retroviral ribozyme transgene or HGF antagonist reduced the growth and angiogenesis of breast tumors in vivo Jiang et al.
Syndecans are transmembrane proteoglycans composed of a core protein and a glycosaminoglycan side chain to which growth factors are attached Szatmari and Dobra, Syndecan-1 is the major syndecan found in epithelial malignancies Szatmari and Dobra, Syndecan-1 ligates with several pro-angiogenic factors such as VEGF, FGFs, Wnt, and HGF, which act as signaling co-receptors Szatmari and Dobra, Expression of syndecan-1 in breast tumors was associated with adverse prognosticators, metastasis, and reduced OS in patients Kind et al.
Besides, stromal syndecan-1 expression increased vessel density and area and promoted the growth and angiogenesis of triple-negative tumors in vivo Maeda et al. Schönfeld et al. showed that targeting syndecan-1 with an antibody-drug conjugate reduced the growth of TNBC in animal models when combined with chemotherapy Schonfeld et al.
An open-label, phase Ib trial evaluating antitumor activity and safety of erdafitinib; a potent and selective pan-FGFR inhibitor, in combination with fulvestrant and palbociclib in patients with metastatic breast cancer is currently recruiting patients NCT The primary objective is to determine safety and tolerability for the combination treatment of erdafitinib with targeted treatments.
Futibatinib is an orally available pan-FGFR inhibitor that is currently being evaluated in a phase II trial as monotherapy and in combination with fulvestrant in patients with locally advanced or metastatic breast cancer harboring FGFR gene amplification NCT The primary outcome of the trial is to determine dose-limiting toxicities during the first two cycles of therapy while secondary outcomes involve the identification of treatment-emergent adverse events TEAEs and objective tumor response.
Rogaratinib is another novel pan-FGFR inhibitor. Rogaratinib showed broad antitumor activity in preclinical studies Grunewald et al. The combination of rogaratinib plus palbociclib and fulvestrant is being assessed in an open-label, multicenter, prospective, phase I dose-escalation clinical trial NCT The primary aims of the study are to assess the recommended phase II dose and the incidence of TEAEs for the combination treatment in patients with metastatic hormone receptor-positive breast cancer who have FGFR-positive tumors.
Additionally, a phase II study is assessing the long-term efficacy and tolerability of rogaratinib in patients who have received the drug in a previous clinical trial and are currently in the continuation phase NCT The selective FGFR-2 inhibitor, RLY, is being evaluated for tolerability and antineoplastic activity in several advanced solid cancers, including the breast NCT The primary outcomes of the study are to determine the maximum tolerated dose of pemigatinib and to assess the pharmacodynamics of the drug.
The I-SPY 2 trial is investigating the effect of trebananib alone or in combination with standard targeted treatments in neoadjuvant settings in patients with breast cancer NCT The main outcome of the trial is to determine the safety and tolerability of NT-I7 in combination with pembrolizumab. Bintrafusp alfa is a first-in-class bifunctional fusion protein targeting TGF-β and programmed death-ligand 1 PD-L1 Paz-Ares et al.
Furthermore, bintrafusp alfa is being assessed as monotherapy in phase II, multicenter, open-label study in participants with TNBC NCT PF, an inhibitor of TGF-βR1, is being evaluated in a phase I dose-escalation study for its safety, tolerability, and pharmacokinetics in patients with advanced solid tumors NCT Table 2 summarizes ongoing clinical trials for selected non-VEGF angiogenic inhibitors in breast cancer.
TABLE 2. Therefore, exploring novel anti-angiogenic therapeutic approaches is of paramount importance for the treatment of aggressive and advanced breast tumors. Such approaches include vascular normalization by targeting pericytes, utilization of miRNAs and extracellular tumor-associated vesicles, using immunotherapeutic drugs, and nanotechnology.
A potential strategy to sensitize tumor endothelium to angiogenesis inhibitors is by targeting pericytes to achieve tumor vascular normalization Lord and Harris, ; Meng et al. Normalization of tumor vasculature prevents cancer cell metastasis, improves the delivery of systemic anticancer therapies, increases the efficacy of local therapies, and enhances recognition by the host immune system.
Pericyte coverage of tumor blood vessels is heterogeneous. In certain tumors, high pericyte coverage of the tumor vasculature causes resistance to anti-angiogenic therapies.
Alternatively, low pericyte coverage detected in the vasculature of certain tumors reduces vascular stability and increases vascular permeability which impairs the delivery of anticancer therapies to tumor cells and allows them to metastasize Meng et al.
Earlier studies showed that combining VEGFR and PDGFR inhibitors targeting endothelial cells and pericytes, respectively, improved the efficacy of anti-angiogenic therapy and reduced tumor growth in animal tumor models Bergers et al.
In a xenograft model of breast carcinoma, tumor vascularization was enhanced by increasing the pericyte-endothelium association via a mechanism involving the TGF-β-fibronectin axis Zonneville et al. In addition, Keskin et al. showed that pericyte targeting in established mouse breast tumors increased Ang-2 expression and that targeting Ang-2 signaling along with pericyte depletion restored vascular stability and decreased tumor growth and metastasis Keskin et al.
Although data from preclinical studies showed that pericyte targeting could be a novel strategy to normalize tumor vasculature, this strategy should be carefully considered as lack of pericyte coverage may disrupt vascular integrity and promote cancer metastasis Lord and Harris, ; Zirlik and Duyster, Assessment of pericyte coverage of tumor vasculature and the identification of the appropriate pericyte-targeted therapy are potential challenges to pericyte targeting Meng et al.
MicroRNAs miRNAs are critical regulators of signaling pathways involved in angiogenesis and cancer metastasis by interacting with the target mRNAs Gallach et al. To date, there are groups of well-characterized miRNAs implicated in regulating endothelial cell function and angiogenesis, making them attractive targets in tumor angiogenesis Gallach et al.
Liang et al. showed that miRNA suppressed breast tumor angiogenesis through targeting HIF-1α and Ang-1 in breast cancer cell lines and animal model. MiRNA inhibited the proliferation, migration, and tube formation of endothelial cells and decreased the microvessel density Liang et al.
Lu et al. reported that miRNAp inhibited tumor invasion and angiogenesis by silencing VEGF-A in breast cancer cells both in vitro and in vivo Lu et al. MiRNAb inhibited proliferation, migration, and tube formation of endothelial cells.
Systemic administration of miRNAb potently suppressed breast tumor growth and vascularization by targeting Akt and downregulating VEGF and c-Myc in breast cancer cells Li et al.
Mimics of miRNA suppressed the proliferation and tube formation of endothelial cells in vitro Wu et al. Moreover, the overexpression of miRNA reduced VEGF and HIF-1α protein levels and suppressed angiogenesis in vivo Wu et al.
Zou et al. showed that miRNA inhibited growth and angiogenesis of TNBC in vivo via post-transcriptional regulation of N-Ras and VEGF Zou et al. Importantly, miRNAs can be transported between cancer cells and stromal cells through extracellular vesicles known to mediate cell-to-cell communication in the tumor microenvironment Kuriyama et al.
Extracellular vesicles are classified into exosomes, microvesicles, and apoptotic bodies based on the size or biogenesis of the vesicles Kuriyama et al. Under hypoxic conditions, tumor cells release extracellular vesicles to a larger extent compared to cells in a normoxic environment Kuriyama et al.
Growing evidence points to the role of tumor-derived extracellular vesicles in tumor angiogenesis of breast cancer. recently reported that extracellular vesicles derived from breast cancer cells are highly enriched with miRNAp which enhanced proliferation and migration of endothelial cells in vitro and angiogenesis and metastasis of breast cancer in vivo Lu et al.
Microvesicles rich in a special VEGF isoform activated VEGFR and induced angiogenesis while being resistant to bevacizumab Feng et al. Exosome-mediated transfer of breast cancer-secreted miRNA efficiently destroyed tight junctions in endothelial monolayers associated with increased vascular permeability Zhou et al.
Few studies showed that extracellular vesicles can be targeted to prevent breast cancer metastasis and restore the activity of anti-angiogenic drugs Zhou et al. Aslan et al. showed that docosahexaenoic acid decreased the expression of pro-angiogenic genes including HIF-1α, TGF-β, and VEGFR in breast cancer cells and their secreted exosomes Aslan et al.
Also, docosahexaenoic acid altered miRNA content in breast cancer cells and their derived exosomes in favor of the inhibition of angiogenesis Aslan et al.
Taken together, miRNAs and extracellular vesicles can be selectively targeted to reduce vascularization in breast cancer providing a novel approach for angiogenesis inhibition Gallach et al.
Normal vasculature is needed for immunosurveillance and efficient detection and killing of cancer cells by immune cells. Disorganized tumor vessels create a selective immune cell barrier limiting the extravasation of immune cells, particularly the cytotoxic T lymphocytes into blood vessels and tumor tissue Yang et al.
Further, hypoxia in the tumor microenvironment promotes lactate accumulation, extracellular acidosis, VEGF overexpression, and VEGFR activation, all of which are known drivers of immune cell tolerance and immunosuppressive status Mendler et al. Endothelial cells are the first to come into contact with immune cells while infiltrating from the circulation into the tumor tissue Solimando et al.
Interestingly, tumor endothelial cells expressed PD-L1 and produced immunosuppressive activity contributing to tumor immune evasion in a mouse model of melanoma Taguchi et al.
Further, leukocyte adhesion was remarkably diminished in tumor vessels Dirkx et al. Tumors secrete angiogenic growth factors that can downregulate endothelial adhesion molecules essential for the interactions with granulocytes, macrophages, and natural killer cells on the vascular endothelium Griffioen, The suppression of these selective adhesion molecules leads to the loss of the adhesive properties of the tumor endothelium thereby impairing immune cell infiltration to tumor tissues.
Solimando et al. showed that junctional adhesion molecule-A JAM-A is an important factor influencing angiogenesis and extra-medullary dissemination in patients with multiple myeloma and its targeting suppressed multiple myeloma-associated angiogenesis both in vitro and in vivo Solimando et al.
Bednarek et al. recently demonstrated that targeting JAM-A with an antagonistic peptide inhibited the adhesion and trans-endothelial migration of breast cancer cells Bednarek et al. In breast cancer, vascular cell adhesion molecule-1 was aberrantly expressed and mediated angiogenesis and metastasis by binding to its ligand α4β1integrin Sharma et al.
Earlier findings also showed that angiogenic stimuli in the microenvironment of breast cancer may influence the expression of endothelial adhesion molecules to prevent leukocyte infiltration to tumor tissue Bouma-Ter Steege et al. Therefore, selective targeting of adhesion molecules and normalizing tumor vasculature could improve immune cell endothelial adhesion and strengthen the antitumor immune response in epithelial tumors, including breast cancer.
A growing body of evidence describes the interplay between immune cells and vasculature in the tumor microenvironment. The immune response and vascular normalization seem to be mutually regulated Fukumura et al.
Normalization of the tumor vasculature improves the infiltration of immune effector cells into tumors enhancing antitumor immune activity Fukumura et al. Likewise, immunotherapy can promote vascular normalization which further improves the effectiveness of immunotherapeutic drugs and response to anti-angiogenic therapies Huang et al.
In preclinical models of breast cancer, immune checkpoint inhibitors induced normalization of tumor vasculature and increased infiltration of immune cells into breast tumors Tian et al.
Together, the combination of anti-angiogenic and immunotherapeutic drugs might be an attractive approach to increase the effectiveness of each class of drugs and reduce the emergence of drug resistance Fukumura et al. The combination treatment has shown encouraging results in various cancer types Ciciola et al.
In a preclinical study, Allen et al. revealed that treatment with a combination of anti-VEGFR-2 and anti-PD-L1 antibodies sensitized tumors to anti-angiogenic therapy and prolonged its efficacy in breast cancer Allen et al.
Li et al. recently demonstrated a dose-dependent synergism for the combined treatment of anti-angiogenic therapy and immune checkpoint blockade Li et al. In this regard, the combination of low-dose anti-VEGFR2 antibody with anti-programmed cell death protein-1 PD-1 therapy normalized tumor vasculature, induced immune cell infiltration, and upregulated PD-1 expression on immune cells in syngeneic breast cancer mouse models.
Additionally, the combined treatment was effective and tolerable in patients with advanced TNBC Li et al. An open-label, randomized, parallel, phase II trial investigated the combination treatment of apatinib, a VEGFR-2 tyrosine kinase inhibitor with the anti-PD-1 monoclonal antibody camrelizumab in patients with advanced TNBC Liu et al.
The results showed that the combination treatment produced favorable therapeutic outcomes in terms of improved objective response rate and PFS which was associated with increased tumor-infiltrating lymphocytes. The adverse events were manageable and included elevated aminotransferases and hand-foot syndrome Liu et al.
Multiple clinical trials of combining anti-angiogenic therapy and immune checkpoint inhibitors are underway Zirlik and Duyster, The nanotechnology-based approach is an emerging strategy for the development of therapies targeting tumor angiogenesis which could improve the current pharmacokinetic profiles of anti-angiogenic drugs and favor their selective accumulation in tumors Banerjee et al.
Radical-containing nanoparticles produced in vitro and in vivo anti-angiogenic activity in a breast cancer model that was mediated by suppressing VEGF in cancer cells Shashni et al. Nanoparticles were also utilized to deliver a combination of therapy for breast cancer to produce anticancer and anti-angiogenic activity Zhao et al.
In a recent study by Gong et al. Table 3 provides a list of novel approaches for targeting vascular growth and angiogenesis in breast cancer.
TABLE 3. Breast cancer is a notable example where anti-angiogenic agents had constantly failed to make a significant impact on the survival of patients in clinical settings. One essential aspect to improve the efficacy of clinically available anti-angiogenic drugs is to better understand the vascular biology of breast cancer at the different stages and molecular types of the disease.
Besides, a greater understanding of the adaptive and intrinsic resistance mechanisms would enhance the proper utilization of angiogenesis inhibitors. Further evaluation for the role of stromal cells within the tumor microenvironment in mediating resistance to anti-angiogenic drugs will improve the efficacy and durability of anti-angiogenic therapy.
Another important facet to consider for the limited activity of angiogenesis inhibitors in breast cancer is the population under examination to allow the identification of breast cancer patients who would benefit most from anti-angiogenic drugs. Furthermore, there are several ongoing efforts to describe novel strategies to inhibit tumor angiogenesis through pericyte targeting, the use of immunotherapy, miRNAs, and the implementation of nanotechnology.
Despite the preclinical success of many of these strategies, limited clinical evidence is available to support their implementation in breast cancer treatment. NMA conceived the manuscript. All authors listed wrote the manuscript and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
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Li, Y. MiRNAb Suppresses Tumor Growth through Simultaneously Inhibiting Angiogenesis and Tumorigenesis by Targeting Akt3. The application of biomarkers is a powerful adjuvant means which are essential for disease identification, early diagnosis and prevention, and drug treatment monitoring.
Biomarkers refer to biochemical indicators of normal physiological or pathogenic processes to furnish the structural or functional changes of systems, organs, tissues, cells and subcells, and can also be used for disease diagnosis, disease stage, or evaluating the safety and efficacy of a drug or regimen among targeted population.
For example, HER2 is a diagnostic indicator for breast cancer typing, and levels of PD-L1 is used to predict the efficacy of immune checkpoint inhibitors ICIs. Despite considerable efforts, there are few biomarkers responding to angiogenesis approved for clinical application.
With the advancement in bio-analytical technology and clinical bio-chemistry, tissue and cell concentrations of some angiogenic mediators, circulating ECs, circulating progenitor cells, CT imaging of blood flow and blood volume have been shown to have potential as biomarkers, but more clinical trials are needed to validate their prospective.
Developing efficient biomarkers for diagnosing the progression and stage of cancer and identifying mechanisms of tumor angiogenesis and drug resistance, in order to benefit drug selection, balance efficacy and toxicity, and simplify anti-cancer therapy.
Actually, due to numerous factors such as the complexity of tumor angiogenesis, heterogeneity and variability of tumors, the unpredictability of response or toxicity, and limitations of preclinical and clinical trials, the development of biomarkers will be a great challenge.
Since the first angiogenic inhibitor bevacizumab approved for treatment, combination therapy based on anti-angiogenic agents has infiltrated anti-tumor field.
Diversified methods in anti-cancer therapy provide more options for clinical treatment and make strong alliances possible. In recent several years, one of the prevalent research direction is the combination of angiogenic inhibitors and immune checkpoint inhibitors, in which better clinical benefits from HCC and RCC patients treated with programmed cell death 1 PD-1 and VEGFR-2 inhibitors than with monotherapy.
At the same time, it can neutralize excess VEGF, reconstruct the vascular system of tumor tissue, normalize vascular network, promote the blood transport of immunosuppressant, inhibit excessive angiogenesis, reduce microvascular density, and limit tumor growth, invasion and metastasis.
Some optimistic results of combination therapy have been achieved in recent years shown in Table 4. For example, in a phase III clinical trial NCT , the combination of bevacizumab with PD-1 inhibitor atezolizumab significantly improved the OS and PFS rates of unresectable HCC patients compared to sorafenib.
As mentioned before, although it has more damage to normal cells, blood vessels and immune system due to the administration with maximum tolerated dosage and poor tissue selectivity, chemotherapy is an irreplaceable method for many advanced patients with cancer metastasis to prolong the survival.
Some relevant clinical trials with positive outcomes have been shown in Table 4. For example, a phase III clinical trial NCT have shown that the addition of atezolizumab anti-PD-L1 greatly extended the OS Another notable therapeutic method is an emerging adjuvant strategy - neoadjuvant chemotherapy NACT , aiming to reduce the tumor and kill invisible metastatic tumor cells through systemic chemotherapy to facilitate subsequent surgery, radiotherapy, and other treatments.
Up to now, various NACT regimens SOX, XELOX, FOLFOX have been suggested with satisfactory clinical results in primary or advanced tumors and lower risk of progression, but some discouraging clinical evidence of NACT also observed in recent years especially breast cancer.
summarized a number of potential mechanisms of chemoresistance in NACT, wherein, it is reported that NACT could stimulate cancer metastasis through inducing angiogenesis, lymphangiogenesis and inflammatory infiltration, altering immune responses and worsening TME, and these changes may induce secondary chemoresistance.
Theoretically, it is promising, but massive efforts are also necessary, some clinical trials are already underway NCT, NCT, NCT, NCT, NCT Apart from the means above, exploiting novel selective multi-targeted kinase inhibitors is one of the current trendy research directions.
In tumor angiogenesis, various angiogenic tyrosine kinases act synergistically to induce an array of intracellular signaling cascades instead of working individually.
In normal tissue, anti-angiogenic molecules can balance the pro-angiogenic factors to maintain the homeostasis of the internal environment.
The active angiogenesis in tumor tissue is related to the over-activation of pro-angiogenic factors and the over-inhibition of anti-angiogenic mediators. Hence, endogenous anti-angiogenic components or their derivatives may be conducive to vascular normalization and therapeutic efficiency.
Recombinant human endostatin is an angiogenic inhibitor with no cytotoxicity approved by the Chinese FDA for treating various cancers, including NSCLC. Angiogenesis is one of the key conditions for the proliferation, invasion, and metastasis of carcinomas and anti-angiogenic treatment has gradually become a prevalent anti-tumor strategy with a criterion of vascular optimization.
But some common issues that cannot be ignored remain to be solved such as insufficient therapeutic efficacy, reproducibility and popularization of treatment modalities.
With an in-depth understanding of tumor angiogenesis, tumor microenvironment, and drug resistance, these problems may be solved in the near future. As an emerging strategy, anti-angiogenic therapy will achieve more clinical benefits for cancer patients and anti-tumor therapy, and facilitate the clinical treatment of non-neoplastic angiogenesis-related diseases as well.
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Hellstrom, A.
Muscular strength progression techniques is a critical requirement Anti-angiigenesis malignant growth, invasion, Anti-angiogenessis metastases. Agents interfering with Muscular strength progression techniques have shown efficacy in the treatment of Remedies for workout-induced muscle soreness Muscular strength progression techniques of solid tumors, such as metastatic mmedicine cancer, non—small-cell Anti-angiogenesis approaches in medicine cancer, and renal approacjes cancer, and are being studied in many more. Each Muscular strength progression techniques the mddicine agents currently approved by the US Food and Drug Administration-bevacizumab Avastinsunitinib Sutentand sorafenib Nexavar -offer challenges to nurses, in terms of assessment and management of toxicity, and to their patients as well: learning and integrating self-care strategies, such as self-assessment and self-administration for sorafenib and sunitinib. This article reviews the recommended dosing, drug interactions, potential side effects, and management strategies for these three agents. Other agents that have antiangiogenesis properties, such as the epidermal growth factor inhibitors, the mTOR inhibitors, bortezomib, and thalidomide will not be addressed. This article will review the classification of agents, their indications, US Food and Drug Administration FDA -approved dosing, as well as class- and drug-specific side effects and their management.
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