Angiogenesis in prostate cancer: its role in disease progression and possible therapeutic approaches

The interaction between cancer cells and their microenvironment is a promising area for the development of novel therapeutic anti-cancer modalities. The formation of new blood vessels, angiogenesis, is an important step in cancer progression. Angiogenesis is a complex multistep process involving close orchestration of endothelial cells, extracellular matrix, and soluble factors. Essentially every step has been found to be regulated by inducers and inhibitors. Prostate cancer has the ability to produce angiogenic factors such as metalloproteinases, vascular endothelial growth factor, fibroblast growth factor 2, transforming growth factor-beta and cyclooxygenase-2. In several studies in prostate cancer an increased microvessel density is associated with poorer prognosis. On the other hand several endogenous inhibitors of angiogenesis have been described in prostate cancer e.g., angiostatin, endostatin, prostate specific antigen (PSA), thrombospondin-1, interleukin 10, interferons and retinoids. The expanding insight in the process of angiogenesis has resulted in a large number of pharmaceutical agents that have been tested in preclinical studies and are currently tested in clinical trials. These agents inhibit endothelial cell proliferation or migration and induce apoptosis. This ultimately will affect the formation of new vessels thereby inducing tumor dormancy. Because antiangiogenic treatment is cytostatic rather than cytotoxic, patients will need long-term therapy to prevent regrowth of the tumor. Prostate cancer is an ideal tumor for antiangiogenic studies because of the availability of a reliable tumor marker, PSA, the indolent clinical course of this cancer and the low rate of proliferation even in metastatic sites. Furthermore, clinical studies showed limited side effects, which is advantageous in this elderly patient group. Whether the ultimate antiangiogenic treatment is effective as a single agent or in combination with radiation therapy, chemotherapy or immunotherapy remains to be determined.     

Angiogenesis and antiangiogenic cancer therapy

Physiologic angiogenesis takes place during tissue growth and repair, during the female reproductive cycle, and during fetal development. Angiogenesis is also required for tumor growth and metastasis and, therefore, represents an exciting target for cancer treatment. Angiogenesis is a complex process that is tightly regulated by pro- and antiangiogenic growth factors. Pathologic angiogenesis is characterized by either excessive (eg. cancer) or inadequate (eg. coronary artery disease) neovascularization. Avascular tumors are severely restricted in their growth potential because of the lack of a blood supply. For tumors to develop in size and metastatic potential they must make an "angiogenic switch" through perturbing the local balance of proangiogenic and antiangiogenic factors. Frequently, tumors overexpress proangiogenic factors, such as vascular endothelial growth factor, allowing them to make this angiogenic switch. Two strategies used in the development of antiangiogenic agents involve the inhibition of proangiogenic factors (eg. anti-vascular endothelial growth factor monoclonal antibodies) as well as therapy with endogenous inhibitors of angiogenesis. Emerging antiangiogenic agents currently in clinical studies are discussed in this review.     

Antiangiogenic strategies, compounds, and early clinical results in breast cancer

Angiogenesis is a multi-step process leading to the formation of new blood vessels from pre-existing vasculature and it is necessary for primary tumor growth, invasiveness and development of metastasis. Experimental and clinical data demonstrated that breast cancer is an angiogenesis-dependent disease and that the vascular endothelial growth factor (VEGF) family plays a key role it being a highly expressed and selective endothelial cell growth factor. Preclinical studies have shown that the angiogenic switch occurs early in the multistage process of breast cancer development. Targeting the molecular pathways involved in tumor progression by biologically-designed treatments is a new therapeutic paradigm aimed to reach cancer growth control. A number of possible therapeutic targets for antiangiogenic agents have been identified. Here we discuss the therapeutic approach based on inhibition of angiogenesis in the context of breast cancer with a focus on the early clinical studies on antiangiogenic agents in advanced disease.     

Anti-angiogenic therapy in pediatric brain tumors: An effective strategy?

Brain tumors are still the leading cause of cancer morbidity and mortality among children, despite different therapeutic options including neurosurgery, chemotherapy and radiation. As angiogenesis is highly crucial in brain tumor growth and progression, numerous clinical trials evaluating diverse anti-angiogenic agents have been described. In the present review, we aimed to answer the question if anti-angiogenic therapy is an effective strategy in the treatment of children with brain tumors. Although some encouraging results have been published of anti-angiogenic therapy targeting vascular endothelial growth factor (VEGF)/VEGF receptor signaling or epidermal growth factor receptor (EGFR), still more insight is warranted to be highly conclusive about the efficacy of anti-angiogenic therapy with currently potential upcoming anti-angiogenic agents in pediatric brain tumors. However, given the need for new therapeutic strategies, multi targeted therapy with anti-angiogenic agents anticipating on possible tumor escape mechanisms could be effective in the future treatment of pediatric brain tumors.     

Drug insight: antiangiogenic therapies for gastrointestinal cancers--focus on monoclonal antibodies

Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy-namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4-Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.     

Angiogenesis and antiangiogenic strategies in pancreatic cancer

Despite numerous advances in the treatment of solid tumors, the prognosis of patients diagnosed with pancreatic cancer remains dismal. Results of both surgical and non-surgical treatment for pancreatic cancer have been extremely disappointing beeause of the tumors propensity to metastasize, failure of chemotherapy to achieve adequate levels within the tumor, and resistance of pancreatic cancer to cytotoxic agents. Current chemotherapeutic agents and radiation treatments rely on the rapidly dividing nature of tumor cells and are limited by their cytotoxic effects on normal cells. The need to exploit the difference between normal and malignant cells has resulted in an enormous amount of research into the process of tumor neovascullarization. New agents are currently being developed that block tumor growth and metastasis through inhibition of angiogenesis. This article reviews the process of angiogenesis and antiangiogenic strategies with a special emphasis on pancreatic cancer.     

Emerging biotechnological strategies for non-viral antiangiogenic gene therapy

Angiogenesis has emerged as a promising target of cancer treatment. With the development of biotechnology, major progress has been made in the exploring effective therapies on targeting tumor angiogenesis over the last 20?years. Gene therapy has attracted considerable interest by virtue of the capabilities of expressing sustained levels of therapeutic agents within cells of the patients. However, the major challenge of gene therapy is the efficient delivery of therapeutic gene to the target site. Compared with viral strategies, non-viral strategies were more acceptable by their widely recognized security and lower side effects. This paper reviews the basic biology of angiogenesis, the potential advantages of antiangiogenic gene therapy, the therapeutic genetic drugs developed through biotechnology, as well as the biotechnological strategies that enhancing non-viral gene therapy targeting to tumor angiogenesis in a more controlled manner, with great respect to RNA interference, ligand-directed vascular targeting strategies, vascular endothelial growth factor pathway and tumor associated macrophages targeting. In conclusion, antiangiogenic gene therapy holds great promise in advancing cancer therapy. Developing better non-viral biotechnological platforms will benefit antiangiogenic targeted cancer gene therapeutic methods, support their evaluation in human clinical trials and realize the actual utilization in the near future.     

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

The success of sorafenib in prolonging survival of patients with hepatocellular carcinoma (HCC) makes therapeutic inhibition of angiogenesis a component of treatment for HCC. To enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, combination of antiangiogenic agents with chemotherapy, radiotherapy or other targeted agents were evaluated. Nevertheless, the use of antiangiogenic therapy remains suboptimal regarding dosage, schedule and duration of therapy. The issue is further complicated by combination antiangiogenesis to other cytotoxic or biologic agents. There is no way to determine which patients are most likely respond to a given form of antiangiogenic therapy. Activation of alternative pathways associated with disease progression in patients undergoing antiangiogenic therapy has also been recognized. There is increasing importance in identifying, validating and standardizing potential response biomarkers for antiangiogenesis therapy for HCC patients. In this review, biomarkers for antiangiogenesis therapy including systemic, circulating, tissue and imaging ones are summarized. The strength and deficit of circulating and imaging biomarkers were further demonstrated by a series of studies in HCC patients receiving radiotherapy with or without thalidomide.     

New approaches in angiogenic targeting for colorectal cancer

Colorectal carcinoma （CRC） is one of the leading causes of cancer death worldwide. In the last decade, the addition of irinotecan and oxaliplatin to standard fluorouracil-based chemotherapy regimens have set the new benchmark of survival for patients with metastatic CRC at approximately 20 too. Despite these advances in the management of CRC, there is a strong medical need for more effective and well-tolerated therapies. The dependence of tumor growth and metastasis on blood vessels makes angiogenesis a rational target for therapy. One of the major pathways involved in this process is the vascular endothelial growth factor （VEGF） and its receptors （VEGFR）. In 2004, the first agent targeting angiogenesis, bevacizumab （BV）, was approved as an adjunct to first-line cytotoxic treatment of metastatic CRC. The role of BV as part of adjuvant treatment and in combination with other targeted therapies is the subject of ongoing trials. However, BV is associated with an increase in the risk of arterial thromboembolic events, hypertension and gastrointestinal perforations and its use must be cautious. Novel VEGFR TK inhibitors with different ranges of nanomolar potencies, selectivities, and pharmacokinetic properties are entering phase 111 trials for the treatment of cancer. Conversely, one of these novel agents, vatalanib, has been shown not to confer survival benefit in first and second-line treatment of advanced CRC. The basis of these findings is being extensively evaluated. Ongoing and new well-designed trials will define the optimal clinical application of the actual antiangiogenic agents, and, on the other hand, intensive efforts in basic research will identify new agents with different antiangiogenic approaches for the treatment of CRC. In this review we discuss and highlight current and future approaches in angiogenic targeting for CRC.     

Classic biphasic pulmonary blastoma: A case report and review of the literature from 2000 to 2022

Classic biphasic pulmonary blastoma (CBPB), a distinct type of lung cancer, is a dual-phasic tumor characterized by the co-existence of low-grade fetal adenocarcinoma and primitive mesenchymal stroma. Accounting for less than 0.1% of surgically removed lung cancers, CBPB commonly presents in individuals during their fourth to fifth decades of life, with smoking as a significant risk factor. The optimal management strategy entails surgical resection, supplemented by chemotherapy to improve prognosis. The frontline chemotherapeutic agents typically include platinum agents and etoposide, with preoperative neoadjuvant chemotherapy potentially enabling operability for initially inoperable cases. In recent years, targeted therapies, such as antiangiogenic agents, have emerged as promising new treatment strategies for CBPB. For patients exhibiting brain metastases or deemed inoperable, radiation therapy proves to be a crucial therapeutic component. CBPB prognosis is adversely affected by factors such as early metastasis, tumor size exceeding 5 cm, and tumor recurrence. In this regard, serological markers have been identified as valuable prognostic indicators. To exemplify, we recount the case of a 44-year-old female patient with CBPB, wherein serum lactate dehydrogenase levels showed significant diagnostic value. This report further incorporates a comprehensive review of CBPB literature from the past 22 years.     

Antiangiogenic therapy for liver metastasis of gastrointestinal malignancies

In about half of the patients with gastrointestinal carcinomas, surgical excision of the primary tumor is not curative because metastasis has already occurred. Recent investigations of metastasis have shown that angiogenesis plays an important role in this process. In solid tumors angiogenesis occurs continuously to provide a blood supply for the proliferating cancer cells. As a new and potent method to control metastasis, antiangiogenic therapy has attracted considerable interest. This therapy inhibits angiogenesis, inducing a dormant state in which tumors cannot grow; the prognosis may thus be remarkably improved. Antiangiogenic agents show a characteristic antitumor effect which is different from that of chemotherapy. Based on our experimental in-vivo data, we conclude that antiangiogenic agents should not be used only for achieving tumor shrinkage, like chemotherapy. These agents should be used to control micrometastases, as the therapeutic effect on such metastasis is excellent. In addition, antiangiogenic agents may be valuable for long-term administration to maintain tumor dormancy, because drug resistance does not develop and these agents have a sustained effect. Combinations with conventional anti-cancer treatments such as chemotherapy, radiotherapy, immunotherapy, or surgery may also be valuable.     

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4⁺ and CD8⁺ T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8⁺ T-cell–dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.     

Anti-angiogenic therapy for colorectal cancer: on the way to getting better!

Based on the theory that tumor growth and metastasis depend on vessels to provide oxygen and nutrients, antiangiogenic therapy was thought as a promising approach to cure cancer. Bevacizumab is the first validated angiogenesis inhibitor, when combined with conventional treatments, which can enhance antitumor effects and prolong survival for patients with colorectal cancer. However, recent years, bevacizumab and other angiogenesis inhibitors are more discussed with drug resistance and the diverse test results. Fortunately, antiangiogenic strategy is more than bevacizumab and more than anti-vascular endothelial growth factor. Dozens of compounds that potently inhibit neoplastic blood vessels formation with different mechanisms have been developed, and many of them are being tested clinically for colorectal cancer. This review will numerate the principal antiangiogenic drugs with various mechanisms, recapitulate the information of studying these drugs for colorectal cancer treatment and try to clue better usage of antiangiogenic therapy for patients with colorectal cancer in the future.     

Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.     

Molecular genetics and targeted therapeutics in biliary tract carcinoma

The primary malignancies of the biliary tract, cholangio-carcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma(BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.     

Recent advances in the treatment of myelodysplastic syndromes

OBJECTIVES: Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorder, which combine ineffective hematopoiesis and evolution to acute myeloid leukemia. Significant progress has been made in the understanding of the disease pathogenesis, diagnostics and classification. Promising new agents and innovative therapeutic strategies are currently used. In this article we will review these achievements and their impact on the treatment of MDS. CURRENT KNOWLEDGE AND KEY POINTS: The pathogenesis of MDS involves abnormalities of the MDS clone itself such as abnormal apoptosis, signalling or epigenetic regulation and abnormalities of the microenvironment such as immune deregulation or increased angiogenesis, which represent potential therapeutic targets. There is currently no standard treatment for MDS and allogeneic stem cell transplantation remains the only curative strategy. However, besides conventional chemotherapy and growth factors, new agents including hypomethylating agents, antiangiogenic drugs, immune modulatory agents have proved effective. FUTURE PROSPECTS AND PROJECTS: The interesting results achieved with these new agents show that it is necessary to continue investigation in order to improve therapeutic strategies in MDS.     

Oral chemotherapy in colorectal cancer treatment: review of the literature

Recent advances in anticancer treatment have focused on the development of oral anticancer agents with the intention of improving the patients' quality of life as well as providing therapeutic alternatives to intravenous chemotherapy. Until agents such as oxaliplatin and irinotecan became available, the treatment of colorectal cancer, one the most common cancers diagnosed in industralized countries, was mainly based on 5-fluorouracil modulation. The overwhelming majority of these new drugs are pyrimidine analogues intended to replace intravenous treatment or to make the therapy more acceptable to the patients. In this article, the use of oral chemotherapy, alone or in combination with radiotherapy, in colorectal cancer is reviewed and updated. The rationale for using oral compounds is discussed and newer agents, such as oral camptothecin analogues and antiangiogenic agents, are presented with the results of their clinical and preclinical developments.     

Transplantation strategies for patients with follicular lymphoma

PURPOSE OF REVIEW: This review summarizes the current status and new developments in autologous and allogeneic transplantation strategies for patients with follicular lymphoma including novel concepts of myeloablative radioimmunotherapy, allogeneic transplantation with dose-reduced conditioning, and in-vivo purging strategies using B-cell-specific antibodies. RECENT FINDINGS: Substantial progress has been made in the clinical management of follicular lymphoma. Besides immunochemotherapeutic approaches combining the B-cell antibody rituximab with conventional chemotherapy regimens, myeloablative chemotherapy or radiochemotherapy supported by autologous peripheral blood stem cell transplantation has been shown to be a highly effective treatment for advanced-stage disease. Dose-reduced conditioning regimens followed by allogeneic transplantation have substantially reduced treatment-related mortality of this approach and ongoing studies are evaluating whether the therapeutic benefit outweighs morbidity and mortality of this potentially curative treatment. Emerging concepts include the use of rituximab for in-vivo purging before reinfusion of autologous stem cells or the application of myeloablative radioimmunotherapy as part of myeloablative consolidation. SUMMARY: The data on myeloablative therapy followed by autologous stem cell transplantation or allogeneic transplantation are encouraging. Allogeneic transplantation with dose-reduced conditioning should be further evaluated within clinical trials, however, in particular for patients with relapsed or refractory lymphoma. Future prospective randomized clinical trials should reevaluate the role of autologous stem cell transplantation in the era of antibody-based therapy and define the role of radioimmunotherapy and of reduced-intensity allogeneic transplantation.     

Prospects in the management of patients with follicular lymphoma beyond first-line therapy

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient’s goals. Preserving quality of life for these patients is essential, given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease.     

A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for antiangiogenic therapy

The traditional view of angiogenesis emphasizes proliferation and migration of vessel wall-associated endothelial cells. However, circulating endothelial progenitor cells have recently been shown to contribute to tumor angiogenesis. Here we quantify the relative contributions of endothelial and endothelial progenitor cells to angiogenesis using a mathematical model. The model predicts that during the early stages of tumor growth, endothelial progenitors have a significant impact on tumor growth and angiogenesis, mediated primarily by their localization in the tumor, not by their proliferation. The model also shows that, as the tumor grows, endothelial progenitors adhere preferentially near the tumor periphery, coincident with the location of highest vascular density, supporting their potential utility as vectors for targeted delivery of therapeutics. Model simulations of various antiangiogenic strategies show that those therapies that effectively target both endothelial and endothelial progenitor cells, either by restoring the balance between angiogenic stimulators and inhibitors or by targeting both types of cells directly, are most effective at delaying tumor growth. The combination of continuous low-dose chemotherapy and antiangiogenic therapy is predicted to have the most significant effect on therapeutic outcome. The model offers new insight into tumor angiogenesis with implications for the rational design of antiangiogenic therapy.