Antiangiogenic Drug Resistance Research Articles

Vessel co-option: a unique vascular-immune niche in liver cancer.

Tumor vasculature is pivotal in regulating tumor perfusion, immune cell infiltration, metastasis, and invasion. The vascular status of the tumor is intricately linked to its immune landscape and response to immunotherapy. Vessel co-option means that tumor tissue adeptly exploits pre-existing blood vessels in the para-carcinoma region to foster its growth rather than inducing angiogenesis. It emerges as a significant mechanism contributing to anti-angiogenic therapy resistance. Different from angiogenic tumors, vessel co-option presents a distinctive vascular-immune niche characterized by varying states and distribution of immune cells, including T-cells, tumor-associated macrophages, neutrophils, and hepatic stellate cells. This unique composition contributes to an immunosuppressive tumor microenvironment that is crucial in modulating the response to cancer immunotherapy. In this review, we systematically reviewed the evidence and molecular mechanisms of vessel co-option in liver cancer, while also exploring its implications for anti-angiogenic drug resistance and the immune microenvironment, to provide new ideas and clues for screening patients with liver cancer who are effective in immunotherapy.

Anti-angiogenic Drug Resistance: Roles and Targeting of Non-coding RNAs (microRNAs and long non-coding RNAs).

Cancers with a high capability for angiogenesis are frequently regarded as being difficult to treat. Anti-angiogenesis drugs are considered the primary therapy for these types of cancers. Due to intrinsic or acquired anti-angiogenesis resistance, therapies result in moderate clinical consequences, despite some hopeful findings. The importance of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding (lncRNAs), and circular RNAs (circRNAs) in drug resistance mechanisms in cancer treatment has been discovered in the previous decade. Anti-angiogenic drug resistance can be influenced by ncRNA dysregulation. Hence, ncRNAs are potential drug resistance targets for new anti-angiogenic drugs in the inhibition of angiogenesis in tumors. Furthermore, some ncRNAs can be employed as biomarkers for anti-angiogenic drug responses and can be used to monitor cancer non-invasively. Combination treatment approaches, combined with routine anti-angiogenesis and some drugs that target the ncRNAs causing resistance, can be potential ways to overcome anti-angiogenesis resistance. For the first time, we explain the mechanisms of anti-angiogenic drug resistance and the related miRNAs and lncRNAs and their signaling pathways in commonly used antiangiogenic drugs implicated in this review article. These ncRNAs could be suggestions for targeting and reducing anti-angiogenic drugs in the future.

Current status and future of anti-angiogenic drugs in lung cancer.

Lung cancer, as a malignant tumor with both high incidence and mortality in China, is one of the major causes of death in our population and one of the major public health problems in China. Effective treatment of lung cancer is a major public health task for all human beings. Angiogenesis plays an important role in the development of tumor, not only as a basic condition for tumor growth, but also as a significant factor to promote tumor metastasis. Therefore, anti-angiogenesis has become a vital means to inhibit tumor development, and anti-angiogenic drugs can rebalance pro- and anti-angiogenic factors to inhibit tumor cells. This article reviews the mechanism of blood vessel formation in tumor tissues and the mechanism of action of different anti-angiogenic drugs, the combination therapy of anti-angiogenic drugs and other anti-tumor drugs, and the mechanism of anti-angiogenic drug resistance.

USP22 upregulates ZEB1-mediated VEGFA transcription in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common solid tumor with high rate of recurrence and mortality. Anti-angiogenesis drugs have been used for the therapy of HCC. However, anti-angiogenic drug resistance commonly occurs during HCC treatment. Thus, identification of a novel VEGFA regulator would be better understanding for HCC progression and anti-angiogenic therapy resistance. Ubiquitin specific protease 22 (USP22) as a deubiquitinating enzyme, participates in a variety of biological processes in numerous tumors. While the molecular mechanism underlying the effects of USP22 on angiogenesis is still needed to be clarified. Here, our results demonstrated that USP22 acts as a co-activator of VEGFA transcription. Importantly, USP22 is involved in maintenance of ZEB1 stability via its deubiquitinase activity. USP22 was recruited to ZEB1-binding elements on the promoter of VEGFA, thereby altering histone H2Bub levels, to enhance ZEB1-mediated VEGFA transcription. USP22 depletion decreased cell proliferation, migration, Vascular Mimicry (VM) formation, and angiogenesis. Furthermore, we provided the evidence to show that knockdown of USP22 inhibited HCC growth in tumor-bearing nude mice. In addition, the expression of USP22 is positively correlated with that of ZEB1 in clinical HCC samples. Our findings suggest that USP22 participates in the promotion of HCC progression, if not all, at least partially via up-regulation of VEGFA transcription, providing a novel therapeutic target for anti-angiogenic drug resistance in HCC.

Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression and Lipid Metabolism Pathway.

Anti-angiogenesis therapy has shown significant anti-tumor effects against a variety of cancers. But resistance to antiangiogenic drugs, intrinsic and evasive, is frequently found in patients during treatment. Here, we report that dihydroartemisinin (DHA), a derivative of the Chinese medicine artemisinin, enhances antiangiogenic drug-induced cytotoxicity in osteosarcoma (OS) cells. Proteomics analysis revealed that DHA treatment significantly affected the activity of the collagen-modifying enzyme lysyl oxidase-like 2 (LOXL2), a regulatory gene associated with poor prognosis of OS. Furthermore, we found that DHA reduced the expression of vascular endothelial growth factor (VEGFA) by downregulating LOXL2. This mechanism was confirmed by QRT-PCR, western blot, and ELISA assays. Correspondingly, vector-enforced expression of LOXL2 markedly reduced VEGFA secretion. Untargeted metabolomic analysis revealed that the lipid metabolism that confers antiangiogenic drug resistance, was also interfered with by DHA. Thus, DHA not only exerts antitumor effects in OS cells directly but also synergizes with the antiangiogenic drug by regulating vascular endothelial growth factor A (VEGFA) expression and lipid metabolism.

Antiangiogenic Strategies in Epithelial Ovarian Cancer: Mechanism, Resistance, and Combination Therapy.

Angiogenesis is one of the hallmarks of cancer and plays a crucial role in carcinogenesis and progression of epithelial ovarian cancer. Antiangiogenic agent is the first approved targeted agent in ovarian cancer. Anti-angiogenic agents mainly include agents target VEGF/VEGFR pathway, such as bevacizumab and agents target receptor tyrosine kinase, and non-VEGF/VEGFR targets of angiogenesis. Antiangiogenic agents demonstrate certain effects in ovarian cancer treatment either as monotherapy or combined with chemotherapy. Unfortunately, antiangiogenic agents, such as bevacizumab, integrated into the ovarian cancer treatment paradigm do not increase cures. Thus, the benefits of anti-angiogenic agents must be carefully weighed against the cost and associated toxicities. Antiangiogenic agents drug resistance and short of predictive biomarkers are main obstacles in ovarian cancer treatment. A combination of poly (ADP-ribose) polymerase inhibitors or immune checkpoint inhibitors might be great strategies to overcome resistance as well as enhance anti-tumor activity of anti-angiogenic drugs. Predictive biomarkers of antiangiogenic agents are in urgent need.

Molecular Mechanisms of Resistance to Anti-Angiogenic Drugs.

The problem of drug resistance in cancer patients has been well in mind from the beginning of modern medicine and oncology treatments with the so called conventional cytotoxic therapy. With the advent of target therapy against tumor angiogenesis and in particular against the vascular endothelial growth factor (VEGF)/VEGF receptor system, researchers thought that resistance could be no more a problem, since the low pattern of proliferation displayed by endothelial cells. However, beside the efficacy demonstrated by antiangiogenic drugs, resistance during prolonged drug treatments appears as a limiting feature. Nowadays, various mechanisms of resistance to antiangiogenic therapeutics have been discovered, either innate and depending on the host, or acquired by the tumor cells, especially as a consequence of induced hypoxia by antiangiogenic drugs and the redundancy of proangiogenic factors in the tumor microenvironment, and other forms of tumor neovascularization, than sprouting angiogenesis. Here, we have reviewed the preclinical and clinical evidence for mechanisms of resistance to antiangiogenic drugs reported so far. The knowledge of the mechanisms underneath antiangiogenic drug resistance could be of help in the choice of the more appropriate drug, the development of novel therapeutic strategies, the design of proper drug combination protocols or new formulations of antiangiogenic strategies.

Deregulation of the circadian clock machinery: A novel biomarker for anti-angiogenic drug resistance in colorectal cancer

Deregulation of the circadian clock machinery: A novel biomarker for anti-angiogenic drug resistance in colorectal cancer

Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy.

The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.

Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance

Intrinsic and evasive antiangiogenic drug (AAD) resistance is frequently developed in cancer patients, and molecular mechanisms underlying AAD resistance remain largely unknown. Here we describe AAD-triggered,lipid-dependent metabolic reprogramming as an alternative mechanism of AAD resistance. Unexpectedly, tumor angiogenesis in adipose and non-adipose environments is equally sensitive to AAD treatment. AAD-treated tumors in adipose environment show accelerated growth rates in the presence of a minimal number of microvessels. Mechanistically, AAD-induced tumor hypoxia initiates the fatty acid oxidation metabolic reprogramming and increases uptake of free fatty acid (FFA) that stimulates cancer cell proliferation. Inhibition of carnitine palmitoyl transferase 1A (CPT1) significantly compromises the FFA-induced cell proliferation. Genetic and pharmacological loss of CPT1 function sensitizes AAD therapeutic efficacy and enhances its anti-tumor effects. Together, we propose an effective cancer therapy concept by combining drugs that target angiogenesis and lipid metabolism.

Discovery of High-Affinity PDGF-VEGFR Interactions: Redefining RTK Dynamics

Nearly all studies of angiogenesis have focused on uni-family ligand-receptor binding, e.g., VEGFs bind to VEGF receptors, PDGFs bind to PDGF receptors, etc. The discovery of VEGF-PDGFRs binding challenges this paradigm and calls for investigation of other ligand-receptor binding possibilities. We utilized surface plasmon resonance to identify and measure PDGF-to-VEGFR binding rates, establishing cut-offs for binding and non-binding interactions. We quantified the kinetics of the recent VEGF-A:PDGFRβ interaction for the first time with KD = 340 pM. We discovered new PDGF:VEGFR2 interactions with PDGF-AA:R2 KD = 530 nM, PDGF-AB:R2 KD = 110 pM, PDGF-BB:R2 KD = 40 nM, and PDGF-CC:R2 KD = 70 pM. We computationally predict that cross-family PDGF binding could contribute up to 96% of VEGFR2 ligation in healthy conditions and in cancer. Together the identification, quantification, and simulation of these novel cross-family interactions posits new mechanisms for understanding anti-angiogenic drug resistance and presents an expanded role of growth factor signaling with significance in health and disease.

Off-tumor targets compromise antiangiogenic drug sensitivity by inducing kidney erythropoietin production

Anti-VEGF drugs are commonly used for treatment of a variety of cancers in human patients, and they often develop resistance. The mechanisms underlying anti-VEGF resistance in human cancer patients are largely unknown. Here, we show that in mouse tumor models and in human cancer patients, the anti-VEGF drug-induced kidney hypoxia augments circulating levels of erythropoietin (EPO). Gain-of-function studies show that EPO protects tumor vessels from anti-VEGF treatment and compromises its antitumor effects. Loss of function by blocking EPO function using a pharmacological approach markedly increases antitumor activity of anti-VEGF drugs through inhibition of tumor angiogenesis. Similarly, genetic loss-of-function data shows that deletion of EpoR in nonerythroid cells significantly increases antiangiogenic and antitumor effects of anti-VEGF therapy. Finally, in a relatively large cohort study, we show that treatment of human colorectal cancer patients with bevacizumab augments circulating EPO levels. These findings uncover a mechanism of desensitizing antiangiogenic and anticancer effects by kidney-produced EPO. Our work presents conceptual advances of our understanding of mechanisms underlying antiangiogenic drug resistance.

Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma.

BackgroundMolecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient.MethodsWe performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed.ResultsA total of 115 metastases were assessed longitudinally in 27 patients. Of these patients, 56% had a heterogeneous response. Progression occurred through the appearance of new metastases in 67%, through progression of existing lesions in 11% and by both in 22% of patients. Despite RECIST-defined progression, 57% of existing metastases remained controlled. The sum of controlled lesions was greater than that of uncontrolled lesions in 47% of patients who progressed only with measurable new lesions.ConclusionsWe identified frequent ITH of anti-angiogenic TKI responses, with subsets of metastases responding and progressing within individual patients. This mirrors molecular ITH and may indicate that anti-angiogenic drug resistance is confined to subclones and not encoded on the trunk of the tumours’ phylogenetic trees. This is clinically important, as patients with small-volume progression may benefit from drug continuation. Predominant progression with new rather than in existing metastases supports a change in disease biology through anti-angiogenics. The results highlight limitations of RECIST in heterogeneous cancers, which may influence clinical trial data validity. This analysis requires prospective confirmation.Trial registrationEuropean Clinical Trials Database(EudraCT): 2009-016675-29, registered 17 March 2010; EudraCT: 2006-004511-21, registered 09 March 2007; EudraCT: 2006-006491-38, registered 22 December 2006.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0729-9) contains supplementary material, which is available to authorized users.

Abstract 3251: A Senescence-like phenotype associates with rapid metastasis promotion following antiangiogenic drug resistance and therapy withdrawal

Abstract Few studies have investigated mechanisms of antiangiogenic drug resistance in mouse models that faithfully recapitulate clinically relevant spontaneous metastatic disease or evaluate the impact of therapy cessation on tumor and stromal cell growth. Generation of such models may be critical to study reported instances of antiangiogenic therapy-induced metastasis in animals that have often proved challenging to confirm in patients. Here we describe the derivation of several human and mouse tumor cell lines obtained from spontaneous metastatic lesions present after surgical removal of primary tumors and following long-term in vivo treatment with sunitinib or axitinib. Selected drug-resistant metastatic (kidney, breast, and melanoma) and non-malignant stromal cell variants (endothelial and fibroblast) were continuously exposed to drug in vitro and then evaluated following both short- and long-term treatment removal (48 hours and 6 months, respectively). Our results show that metastatic drug-resistant cells receiving sustained treatment were re-sensitized to therapy upon orthotopic re-implantation into treatment-naïve animals, suggesting a predominant host-mediated role in therapy failure. However, significant increases in tumor growth and metastatic potential were observed in all models when cells were re-implanted and therapy stopped, suggesting a tumor-dependent pro-metastatic mechanism activated by therapy withdrawal. Whole genome expression analysis for resistant cells on and off treatment revealed reversible and irreversible gene changes implicating a senescence-like phenotype capable of influencing metastatic potential. Senescent-like characteristics included increased cell size, decreased proliferation, cell cycle check-point protein alteration, and therapy-induced SA-β-galactosidase expression, depending on the cell line. Critically, antiangiogenic therapy could induce a senescence associated secretory phenotype (SASP) in both tumor and stroma cells which reversed or persisted following therapy cessation in certain instances. Importantly, we found that interleukin-6 (IL-6) - a major component of the SASP - was upregulated in resistant tumor and stroma cells, but only remained upregulated in stromal cells following therapy withdrawal. These results suggest that antiangiogenic treatment-induced senescence-like changes may contribute to treatment failure and contribute to pro-metastatic growth depending on cell origin (i.e., tumor or stroma) and whether treatment is sustained or stopped. Citation Format: Michalis Mastri, Amanda Tracz, Biao Liu, Christina R. Lee, John ML Ebos. A Senescence-like phenotype associates with rapid metastasis promotion following antiangiogenic drug resistance and therapy withdrawal. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3251.

Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance.

Angiogenesis plays a crucial role in tumor growth, with an undisputed contribution of resident endothelial cells (EC) to new blood vessels in the tumor. Here, we report the definition of a small population of vascular-resident stem/progenitor-like EC that contributes predominantly to new blood vessel formation in the tumor. Although the surface markers of this population are similar to other ECs, those from the lung vasculature possess colony-forming ability in vitro and contribute to angiogenesis in vivo These specific ECs actively proliferate in lung tumors, and the percentage of this population significantly increases in the tumor vasculature relative to normal lung tissue. Using genetic recombination and bone marrow transplant models, we show that these cells are phenotypically true ECs and do not originate from hematopoietic cells. After treatment of tumors with antiangiogenic drugs, these specific ECs selectively survived and remained in the tumor. Together, our results established that ECs in the peripheral vasculature are heterogeneous and that stem/progenitor-like ECs play an indispensable role in tumor angiogenesis as EC-supplying cells. The lack of susceptibility of these ECs to antiangiogenic drugs may account for resistance of the tumor to this drug type. Thus, inhibiting these ECs might provide a promising strategy to overcome antiangiogenic drug resistance. Cancer Res; 76(11); 3200-10. ©2016 AACR.

Current standards and new concepts in MRI and PET response assessment of antiangiogenic therapies in high-grade glioma patients.

Despite multimodal treatment, the prognosis of high-grade gliomas is grim. As tumor growth is critically dependent on new blood vessel formation, antiangiogenic treatment approaches offer an innovative treatment strategy. Bevacizumab, a humanized monoclonal antibody, has been in the spotlight of antiangiogenic approaches for several years. Currently, MRI including contrast-enhanced T1-weighted and T2/fluid-attenuated inversion recovery (FLAIR) images is routinely used to evaluate antiangiogenic treatment response (Response Assessment in Neuro-Oncology criteria). However, by restoring the blood-brain barrier, bevacizumab may reduce T1 contrast enhancement and T2/FLAIR hyperintensity, thereby obscuring the imaging-based detection of progression. The aim of this review is to highlight the recent role of imaging biomarkers from MR and PET imaging on measurement of disease progression and treatment effectiveness in antiangiogenic therapies. Based on the reviewed studies, multimodal imaging combining standard MRI with new physiological MRI techniques and metabolic PET imaging, in particular amino acid tracers, may have the ability to detect antiangiogenic drug susceptibility or resistance prior to morphological changes. As advances occur in the development of therapies that target specific biochemical or molecular pathways and alter tumor physiology in potentially predictable ways, the validation of physiological and metabolic imaging biomarkers will become increasingly important in the near future.

CGKRK-modified nanoparticles for dual-targeting drug delivery to tumor cells and angiogenic blood vessels

Antiangiogenic therapy shows great advantages in clinical cancer treatment while no overall survival has been achieved. The compromised results were mainly contributed by intrinsic/acquired antiangiogenic drug resistance and increased local invasion or distant metastasis after antiangiogenic therapy. Here we constructed a CGKRK peptide-modified PEG-co-PCL nanoparticulate drug delivery system (DDS), aiming at targeting both tumor angiogenic blood vessels and tumor cells to achieve enhanced anti-tumor activity as well as holding a great potential to overcome the drawbacks of antiangiogenic therapy alone. The obtained CGKRK-functionalized PEG-co-PCL nanoparticles (CGKRK-NP) with a particle size of 117.28 ± 10.42 nm and zeta potential of −15.7 ± 3.32 mV, exhibited an enhanced accumulation via an energy-dependent, lipid raft/caveolae-mediated endocytosis with the involvement of microtubules in human umbilical vein endothelial cells (HUVEC) and an energy-dependent, lipid raft/caveolae-mediated endocytosis with the participation of Golgi apparatus in human U87MG cells. Using coumarin-6 as the fluorescence probe, in vitro U87MG tumor spheroids assays showed that CGKRK-NP effectively penetrated into the tumor spheroids. Selective accumulation and extensive bio-distribution of CGKRK-NP at tumor site was confirmed by in vivo imaging and tumor section analysis. After drug loading, CGKRK-NP enhanced cytotoxicity and apoptosis induction activity of the loaded PTX on both HUVEC cells and U87MG cells and improved its inhibition effect on the growth of U87MG tumor spheroids. The smallest tumor volume was achieved by those mice bearing subcutaneous U87MG tumor following the treatment of PTX-loaded CGKRK-NP. The findings here indicated that CGKRK peptide-functionalized nanoparticulate DDS could be used as an effective tumor angiogenic blood vessels and tumor cells dual-targeting DDS and might provide a great promising approach for reducing the disadvantages of antiangiogenic therapy alone.

Vessel co‐option in primary human tumors and metastases: an obstacle to effective anti‐angiogenic treatment?

Angiogenesis has been regarded as essential for tumor growth and progression. Studies of many human tumors, however, suggest that their microcirculation may be provided by nonsprouting vessels and that a variety of tumors can grow and metastasize without angiogenesis. Vessel co-option, where tumor cells migrate along the preexisting vessels of the host organ, is regarded as an alternative tumor blood supply. Vessel co-option may occur in many malignancies, but so far mostly reported in highly vascularized tissues such as brain, lung, and liver. In primary and metastatic lung cancer and liver metastasis from different primary origins, as much as 10–30% of the tumors are reported to use this alternative blood supply. In addition, vessel co-option is introduced as a potential explanation of antiangiogenic drug resistance, although the impact of vessel co-option in this clinical setting is still to be further explored. In this review we discuss tumor vessel co-option with specific examples of vessel co-option in primary and secondary tumors and a consideration of the clinical implications of this alternative tumor blood supply.Both primary and metastatic tumors use preexisting host tissue vessels as their blood supply. Tumors may grow to a clinically detectable size without angiogenesis and makes them less likely to respond to drugs designed to target the abnormal vasculature produced by angiogenesis, but further studies to explore the biological and clinical implication of these co-opted vessels is needed.

The possible role of chemotherapy in antiangiogenic drug resistance

The use of antiangiogenic drugs for cancer treatment was welcomed because of the hypothesis that they would be much less likely to lose their therapeutic activity as a result of tumor-acquired resistance over time. Unfortunately, the clinical experience has shown that acquired resistance to antiangiogenic therapeutic strategies is possible since many patients whose tumors initially respond to drugs such as bevacizumab (a monoclonal antibody against VEGF), sorafenib, or sunitinib (tyrosine kinase inhibitors targeting VEGF receptors and PDGF receptors) or metronomic chemotherapy (e.g. low dose cyclophosphamide) become nonresponsive, often within months of therapy initiation. Indeed, the role of associated antineoplastic chemotherapy in antiangiogenic resistance seems to be ignored by the previous studies and the real part played by these drugs has to be written yet. The studies undertaken on antiangiogenic resistance mainly involved mechanisms directly related to the antiangiogenic drugs alone and as such lead one to ask whether the acquired resistance to angiogenesis pathway-targeting might also be mediated by the chemotherapeutic drugs usually associated (at least into the clinic) with these types of drugs.The proposed hypothesis is concerning the possibility that the acquired resistance to antiangiogenic therapy could be actively and heavily modulated by the choice of the associated chemotherapeutic drug. The chemotherapeutic compounds may delay or accelerate the process through the induction, upregulation or downregulation of pro-angiogenic or anti-angiogenic factors or their receptors in the tumor, endothelial and other type of cells of the tumor microenvironment. In conclusion, the consequences of our hypothesis could be promptly translated into the preclinical studies and verified in clinical trials, involving cancer patients resistant to chemotherapy plus antiangiogenic drug schedules.

Nowotworowe naczynia krwionośne

Growth of tumors usually depends on the development of the tumor’s own vasculature. Small avascular tumors (1–2 mm3) cannot continue growth provided an equilibrium between pro-angiogenic and anti-angiogenic factors is maintained within the tumor environment. Angiogenesis is not the only factor responsible for tumor blood vessels forming, as vasculogenic mimicry plays an equally substantial role in this process. Vessel-like structures formed during this process are made up from cancer cells, macrophages and mast cells. Certain neoplasms are capable of growing without developing their own vasculature; instead they secure growth via normal blood vessels of the host. Slowed-down blood flow through an abnormally built tumor vascular network is the main reason for cancer cells’ underoxygenation (hypoxia). Defective blood vessels, with hypoxia resulting, play a major role in tumor progression. Underoxygenation induces formation of novel vessels and these new defective vessels are in turn the principal reason for hypoxia. The latter increases cancer cells’ malignancy and invasiveness. A particular process, called transdifferentiation, takes place in tumor vasculature when hypoxia is present and involves neoplastic cells transforming into endothelial cells. Since growth of a tumor is dependent on its own blood supply, inhibition of such vascular network growth and/or damage to this network should exert a strong impact on tumor growth. Long-term administration of anti-angiogenic drugs, however, encounters unexpected problems. Anti-angiogenic drug resistance, together with paradoxical stimulation of invasiveness and metastasis by these drugs, has lately become a dominant issue in anticancer therapy.