Prostate cancer (PCa) is the second leading cause of cancer-related death among men in most Western countries. Current therapies for PCa are limited, often ineffective, and associated with significant side effects. As a result, there is a growing interest in exploring new therapeutic agents, particularly from the polyphyletic group of algae, which offers a promising source of compounds with anticancer properties. Our research group has focused on investigating the effects of a novel oleoresin from Gracilaria chilensis, known as Gracilex®, as a potential therapeutic agent against PCa using both in vitro and in vivo models. Our findings indicate that Gracilex® exhibits a time- and dose-dependent inhibitory effect on cell survival in LNCaP and PC-3 PCa, reducing viability by over 50% and inducing apoptosis, as evidenced by a significant increase in activated caspase-3 expression in both cell lines. Moreover, Gracilex® significantly reduces the proliferation rate of both LNCaP and PC-3 prostate cancer cell lines, as evidenced by a marked decrease in the growth curve slope (p = 0.0034 for LNCaP; p < 0.0001 for PC-3) and a 40–50% reduction in the proportion of Ki-67-positive PCa cells. In addition, Gracilex® significantly reduces in vitro cell migration and invasion in LNCaP and PC-3 cell lines. Lastly, Gracilex® inhibits tumor growth in an in vivo xenograft model, an effect that correlates with the reduced PCa cell proliferation observed in tumor tissue sections. Collectively, our data strongly support the broad antitumoral effects of Gracilex® on PCa cells in vitro and in vivo. These findings advance our understanding of its potential therapeutic role in PCa and highlight the relevance of further investigating algae-derived compounds for cancer treatment.

Connexins (Cxs) have the ability to form channels that allow the exchange of ions/metabolites between adjacent cells (gap junction channels, GJC) or between the intra- and extra-cellular compartments (hemichannels, HC). Cxs were initially classified as tumor suppressors. However, more recently, it has been shown that Cxs exert anti- and pro-tumorigenic effects depending on the cell and tissue context. In prostate cancer (PCa), the expression and functionality of Cxs remain highly controversial. Here, we analyzed the expression pattern of Cx26, Cx32, Cx37, Cx40, Cx43 and Cx45 in PCa cell lines with increasing levels of tumor aggressiveness (LNCaP < LNCaP-C4-2 < Du-145 < PC-3). In addition, GJ and HC activities were evaluated in the PCa cell lines using dye coupling and dye uptake assays, respectively. Lastly, the cellular localization of Cx26, Cx32, and Cx43 was analyzed in LNCaP and PC-3 cell lines using immunofluorescence analyses. Our results showed a positive association between the mRNA levels of Cx26, Cx37 and Cx45 and the degree of aggressiveness of PCa cells, a negative association in the case of Cx32 and Cx43, and no clear pattern for Cx40. At the protein level, a negative relationship between the expression of Cx26, Cx32 and Cx43 and the degree of aggressiveness of PCa cell lines was observed. No significant differences were observed for the expression of Cx37, Cx40, and Cx45 in PCa cell lines. At the functional level, only LNCaP cells showed moderate GJ activity and LNCaP and LNCaP-C4-2 cells showed HC activity. Immunofluorescence analyses confirmed that the majority of Cx26, Cx32, and Cx43 expression was localized in the cytoplasm of both LNCaP and PC3 cell lines. This data indicated that GJ and HC activities were moderately detected only in the less aggressive PCa cells, which suggest that Cxs expression in highly aggressive PCa cells could be associated to channel-independent roles.

Glut(s) expression PC-3 cell line-derived xenograft model.

Gene Set Enrichment Analysis (GSEA) from RNA sequencing data of PC3 cells stimulated with fructose or glucose.

Supplementary Fig. 5. Histone marks expression associated with resistance to sunitinib

Medicinal plants have been used since prehistoric times and continue to treat several diseases as a fundamental part of the healing process. Inflammation is a condition characterized by redness, pain, and swelling. This process is a hard response by living tissue to any injury. Furthermore, inflammation is produced by various diseases such as rheumatic and immune-mediated conditions, cancer, cardiovascular diseases, obesity, and diabetes. Hence, anti-inflammatory-based treatments could emerge as a novel and exciting approach to treating these diseases. Medicinal plants and their secondary metabolites are known for their anti-inflammatory properties, and this review introduces various native Chilean plants whose anti-inflammatory effects have been evaluated in experimental studies. Fragaria chiloensis, Ugni molinae, Buddleja globosa, Aristotelia chilensis, Berberis microphylla, and Quillaja saponaria are some native species analyzed in this review. Since inflammation treatment is not a one-dimensional solution, this review seeks a multidimensional therapeutic approach to inflammation with plant extracts based on scientific and ancestral knowledge.

BACKGROUND:Over the last 20 years, fructose has gradually emerged as a potential metabolic substrate capable of promoting the growth and progression of various cancers, including prostate cancer (PCa). The biological and molecular mechanisms that underlie the effects of fructose on cancer are beginning to be elucidated. METHODS:This review summarizes the biological function of fructose as a potential carbon source for PCa cells and its role in the functionality of the male reproductive tract under normal conditions. RESULTS:The most recent biological advances related to fructose transport and metabolism as well as their implications in PCa growth and progression suggest that fructose represent a potential carbon source for PCa cells. Consequently, fructose derivatives may represent efficient radiotracers for obtaining PCa images via positron emission tomography and fructose transporters/fructose-metabolizing enzymes could be utilized as potential diagnostic and/or predictive biomarkers for PCa. CONCLUSION:The existing data suggest that restriction of fructose from the diet could be a useful therapeutic strategy for patients with PCa.

Biological/clinical parameters (patient age, PSA levels, Gleason score) and glucose and fructose levels in benign and PCa patients.

Downregulation of Glut-5 expression in PC-3 cells using the siRNA methodology.

Background: Prostate cancer (PCa) represents one of the most frequent malignancies and the fifth leading cause of cancer death in adult men worldwide. PCa mortality rates have been declining in several Western countries; one of the possible reasons may be related to the application of prostate-specific antigen early detection policies. These early detection protocols increase PCa-specific patient survival; however, a high percentage of these cases corresponds to low-risk PCa that grows very slowly and is unlikely to metastasize to threaten survival. Many low-risk PCa patients receive aggressive therapies, such as radical prostatectomy and radiotherapy, that are costly for patients and/or health systems and generate side effects that affect the quality of life. An alternative to surgery and radiotherapy treatments for low-risk PCa is active surveillance (AS), a strategy based on close disease monitoring and intervention only if the disease progresses. However, proper identification of low-risk PCa patients at the time of diagnosis is essential for the effectiveness AS. The selection of AS candidates remains challenging; thus, effective prognostic biomarkers are needed. Summary: This review article addresses the characteristics of the current and emerging PCa prognostic biomarkers, including tests available for tissue, blood, and urine analyses, for the appropriate selection of PCa patients for AS. In addition, and based on published literature, we performed a selection of potential new biomarkers that can distinguish low-risk PCa. Key Messages: The literature search yielded four tissue-based tests, two blood-based tests, and six urine-based tests that can be used to determine PCa risk classification. However, most available tests are expensive; thus, cost-effective analyses are needed in order to obtain the approval of government agencies and to be financed by the health systems. Available prognostic urine tests have shown great progress over the last years, and they have the advantage of being minimally invasive; therefore, they may become a routine disease progression test for patients under AS. In addition, new research conducted in the last decade has shown promising biomarkers, including mRNA, miRNA, long noncoding RNA, and metabolites, that could improve existing tests or allow the development of new tools for AS patient selection.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). Interferon (IFN)-β constitutes one of the first-line therapies to treat MS, but has limited efficacy due to the injectable systemic administration, short half-life, and limited CNS access. To address these limitations, we developed IFN-β-loaded chitosan/sulfobutylether-β-cyclodextrin nanoparticles (IFN-β-NPs) for delivery of IFN-β into the CNS via the intranasal (i.n.) route. The nanoparticles (NPs) (≈200 nm, polydispersity ≈0.1, and zeta potential ≈20 mV) were prepared by mixing two aqueous solutions and associated human or murine IFN-β with high efficiency (90%). Functional in vitro assays showed that IFN-β-NPs were safe and that IFN-β was steadily released while retaining biological activity. Biodistribution analysis showed an early and high fluorescence in the brain after nasal administration of fluorescent probe-loaded NPs. Remarkably, mice developing experimental autoimmune encephalomyelitis (EAE), an experimental model of MS, exhibited a significant improvement of clinical symptoms in response to intranasal IFN-β-NPs (inIFN-β-NPs), whereas a similar dose of intranasal or systemic free IFN-β had no effect. Importantly, inIFN-β-NPs treatment was equally effective despite a reduction of 78% in the total amount of weekly administered IFN-β. Spinal cords obtained from inIFN-β-NPs-treated EAE mice showed fewer inflammatory foci and demyelination, lower expression of antigen-presenting and costimulatory proteins on CD11b+ cells, and lower astrocyte and microglia activation than control mice. Therefore, IFN-β treatment at tested doses was effective in promoting clinical recovery and control of neuroinflammation in EAE only when associated with NPs. Overall, inIFN-β-NPs represent a potential, effective, non-invasive, and low-cost therapy for MS.

Abstract Introduction: Carcinoma-associated fibroblasts (CAFs) play a key role during cancer progression through several mechanisms, including the induction of the epithelial-mesenchymal transition (EMT) program, giving cancer cells the ability to initiate metastasis. As the cells progress to the mesenchymal state they acquire properties of cancer stem cells (CSC) or mesenchymal stem cell (MSC). However, the contribution of the CAFs in the acquisition of the differential stemness is largely unknown. Here, we studied the stemness features of prostate cancer cells (PC3) during the EMT program induced by fibroblasts obtained from patients with nonmetastatic prostate cancer (CAF) and bone metastatic prostate cancer (mCAF). Materials and Methods: PC3 cells were incubated with conditioned medium (CM) of CAF and mCAF for 7,14, and 21 days to induced EMT. The presence of putative CSCs and MSCs was determined by qPCR, immunocytochemistry and Western blot for the expression of CSCs and MSCs markers, respectively, and functionally evaluated by the ability to perform adipogenic, chondrogrenic, and osteogenic differentiation (MSCs) and in vitro spheroids formation and clonogenic assay (CSCs). Results and Discussion: Our results demonstrate that cancer cells treated with CM-CAF undergo to a partial EMT program, exhibiting certain mesenchymal traits and enriched for cancer stem cells (CSCs). On the other hand, tumor cells exposed to CM-mCAF, exhibited a full EMT conversion with the greater abilities to migrate and invade in vitro and in vivo. This suggests that CAFs and mCAFs induce differential EMT programs in prostate cancer cells, which leads them to acquire CSCs or MSC features enhancing the metastatic capabilities. (FONDECYT 1150397.) Citation Format: Muriel A. Nuñez, Javier Cerda-Infante, Marianela Sánchez, Paula Sotomayor, Alejandro S. Godoy, Viviana P. Montecinos. Stemness features of prostate cancer cells induced by carcinoma-associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B007.

Prostate cancer (PCa) is a disease of increasing medical significance worldwide. In developed countries, PCa is the most common non-skin cancer in men, and one of the leading causes of cancer-related deaths. Exercise is one of the environmental factors that have been shown to influence cancer risk. Moreover, systemic reviews and meta-analysis have suggested that total physical activity is related to a decrease in the risk of developing PCa. In addition, epidemiological studies have shown that exercise, after diagnosis, has benefits regarding PCa development, and positive outcome in patients under treatment. The standard treatment for locally advanced or metastatic PCa is Androgen deprivation therapy (ADT). ADT produces diverse side effects, including loss of libido, changes in body composition (increase abdominal fat), and reduced muscle mass, and muscle tone. Analysis of numerous research publications showed that aerobic and/or resistance training improve patient's physical condition, such us, cardiorespiratory fitness, muscle strength, physical function, body composition, and fatigue. Therefore, exercise might counteract several ADT treatment-induced side effects. In addition of the aforementioned benefits, epidemiological, and in vitro studies have shown that exercise might decrease PCa development. Thus, physical activity might attenuate the risk of PCa and supervised exercise intervention might improve deleterious effects of cancer treatment, such as ADT side effects. This review article provides evidence indicating that exercise could complement, and potentiate, the current standard treatments for advanced PCa, probably by creating an unfavorable microenvironment that can negatively affect tumor development, and progression.

Activation of glucose transporter-1 (Glut-1) gene expression is a molecular feature of cancer cells that increases glucose uptake and metabolism. Increased glucose uptake is the basis for the clinical localization of primary tumors using positron emission tomography (PET) and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) as a radiotracer. However, previous studies have demonstrated that a considerable number of cancers, which include prostate cancer (CaP), express low to undetectable levels of Glut-1 and that FDG-PET has limited clinical applicability in CaP. This observation could be explained by a low metabolic activity of CaP cells that may be overcome using different hexoses, such as fructose, as the preferred energy source. However, these hypotheses have not been examined critically in CaP. This review article summarizes what is currently known about transport and metabolism of hexoses, and more specifically fructose, in CaP and provides experimental evidences indicating that CaP cells may have increased capacity to transport and metabolize fructose in vitro and in vivo. Moreover, this review highlights recent findings that allow better understanding of how metabolism of fructose may regulate cancer cell proliferation and how fructose uptake and metabolism, through the de novo lipogenesis pathway, may provide new opportunities for CaP early diagnosis, staging, and treatment.

Introduction PET-scanning can detect primary tumours relaying on their high glucose uptake ability through overexpression of the glucose transporter Glut-1. However, this method has shown limited clinical applicability for prostate cancer (PCa) diagnosis, suggesting that PCa cells do not use glucose as its primary source of energy. Preliminary data from our laboratory has shown overexpression of the fructose transporter Glut-5 in PCa cell lines and in clinical specimens of PCa, which suggest that fructose could play an important role in PCa biology. Material and methods We analysed the effect of fructose on aggressiveness and metabolic reprogramming in benign prostate epithelial and PCa cell lines. Cells were incubated with glucose or fructose in the media for 24, 48, and 72 hour and then we evaluated: 1) the proliferative rate of benign and PCa cells, 2) the invasion and migration capacity of PCa cells, and 3) the mRNA levels of the enzymes involved in glycolysis, pentose phosphate and de novo lipogenesis pathways using real-time PCR in PCa cells. The effect of fructose on tumour growth was analysed by a PC3 cell line xenograft in immunosuppressed NSG mice. 15% fructose was added to the drinking water for 8 weeks. Tumour weight and the expression of glycolytic enzymes by qPCR was evaluated with respect to the control (water without additives). Results and discussions PCa cells incubated with fructose or glucose, showed similar proliferative rate, invasion and migration capacities. However, fructose evokes a different expression profile of the enzymes involve in glycolysis, pentose phosphate and de novo lipogenesis pathways. Fructose promotes tumour growth of PC3 cells in the NSG mice. Conclusion Our data suggest that fructose could play an important role in PCa pathophysiology, promoting proliferation and migration of PCa cells in vitro , and increasing tumour growth in vivo thanks to a reprogram in their metabolism that allows PCa cells to use fructose as effectively as glucose.

Introduction The clinical localization of primary cancers and sites of metastasis by positron emission tomography (PET) is based on the enhanced cellular uptake of 2-deoxy-2-[ 18 F]-fluoro-d-glucose (FDG). In prostate cancer (CaP), however, FDG-PET imaging has shown limited clinical applicability. This striking difference suggests that CaP cells utilise hexoses other than glucose, such as fructose, as the principal energy source. The purpose of this study was to determine whether or not fructose is a/the principal source of energy for CaP cells. Material and methods We determined the glucose and fructose concentration in serum from benign and CaP patients, the protein expression of Glut1, Glut5 and Glut9 and mRNA expression of Glut1, Glut5, Glut7, Glut9 and Glut11 in clinical specimens of benign and malignant prostate tissue using immunostaining and qRT-PCR. Moreover, mRNA and protein expression for the glucose transporters was analysed in vitro in benign (RWPE-1) and malignant (LNCaP, LNCaP-C4-2, DU-145, and PC3) CaP cell lines using qRT-PCR and western blot. Fructose and glucose uptake was measured in vitro in prostate cell lines using radiolabelled d-[U- 14 C]-fructose or 2-[1,2–3 hour]-deoxy-d-[ 3 H]-glucose, respectively. The effect of fructose and glucose on mitochondrial metabolism was analysed in prostate cell lines using seahorse analysis and the effect of fructose on tumour growth was analysed in vivo using a PC3 cell line xenograft model using immunosuppressed NSG mice. Results and discussions Fructose concentration was elevated in CaP patients compared to benign and no difference in glucose levels was observed. The expression of the fructose transporters, Glut5 and Glut9, was increased in CaP cell lines and in human CaP tissues compared to benign cell lines and benign prostate tissues, respectively. Glut1 expression, however, did not differ between benign and malignant human prostate cells. Transport assays demonstrated that CaP cell lines have a higher capacity to transport fructose compared to benign cell lines. However, glucose uptake was not altered between benign and malignant human prostate cell lines. ATP levels, basal and maximal respiration in bening and CaP cells were similar in the presence of fructose or glucose. Lastly, fructose was able to increase the growth rate, size and weight of the tumours in the NSG mice compared to controls (without fructose). Conclusion Our results indicate that fructose may represent an alternative energy source for CaP cells and may promote CaP tumour growth of CaP cells in vivo .

Introduction Carcinoma-associated fibroblasts (CAFs) play a key role during cancer progression through several mechanisms including the induction of the epithelial-mesenchymal transition (EMT) program, giving cancer cells the ability to initiate metastasis. As the cells progress to the mesenchymal state acquire properties of Cancer Stem Cells (CSC) or Mesenchymal Stem Cell (MSC). However, the contribution of the CAFs in the acquisition of the differential stemness is largely unknown. Here, we studied the stemness features of prostate cancer cells (PC3) during the EMT program induced by fibroblasts obtained from patients with non-metastatic prostate cancer (CAF) and bone metastatic prostate cancer (mCAF). Material and methods PC3 cells were incubated with conditioned medium (CM) of CAF and mCAF for 7,14 and 21 days to induced EMT. The presence of putative CSCs and MSCs was determined by qPCR, immunocytochemistry and western blot for the expression of CSCs and MSCs markers respectively and functionally evaluated by the ability to perform adipogenic, chondrogrenic and osteogenic differentiation (MSCs) and in vitro spheroids formation and clonogenic assay (CSCs). Results and discussions Our results demonstrate that cancer cells treated with CM-CAF undergo to a partial EMT program, exhibiting certain mesenchymal traits and enriched for cancer stem cells (CSCs). On the other hand, tumour cells exposed to CM-mCAF, exhibited a full EMT conversion with the greater abilities to migrate and invade in vitro and in vivo . Conclusion This suggests that CAFs and mCAFs induce differential EMT programs in prostate cancer cells, which leads them to acquire CSCs or MSC features enhancing the metastatic capabilities.

Abstract The elevated level of glucose uptake and metabolism in cancers is the basis for the clinical localization of primary cancers and sites of metastasis by positron emission tomography (PET scanning), based on the enhanced cellular uptake of 2-deoxy-2-[18F]-fluoro-D-glucose (FDG). In prostate cancer (CaP), however, FDG-PET imaging has shown limited clinical applicability. This striking difference suggests that CaP cells utilize hexoses other than glucose, such as fructose, as the principal energy source. The purpose of this study was to determine whether or not fructose is a/the principal source of energy for CaP cells. mRNA and protein expression for the glucose transporter Glut-1 and fructose transporters Glut-2, Glut-5, Glut-7, Glut-9 and Glut-11 was analyzed in benign (PWR-1E, RWPE-1) and malignant (LNCaP, vCaP, LNCaP-C4-2, DU-145, and PC-3) human prostate cell lines using qRT-PCR and western blot, respectively. In addition, Glut(s) protein expression was analyzed on a tissue microarray containing 200 formalin-fixed paraffin-embedded benign and malignant human prostate tissues using immunohistochemistry. Fructose and glucose uptake was measured in vitro in benign and malignant human prostate cell lines using radiolabelled D-[U-14C]-fructose or 2-[1,2-3H]-deoxy-D-[3H]-glucose, respectively. Lastly, the effect of fructose or glucose on the levels of ATP, mitochondrial metabolism, and expression of the enzymes hexokinase-2 (HK2), type-C fructokinase (KHK-C), pyruvate kinase M2 (PKM2) and type-A lactate dehydrogenase (LDH-A) was analyzed in benign and malignant human prostate cell lines using chemiluminescence, seahorse, and qRT-PCR analyses, respectively. Our results indicated that expression of the fructose transporters, Glut-5 and Glut-9, was increased in CaP cell lines and in human CaP tissues compared to benign cell lines and benign prostate tissues, respectively. Glut-1 expression, however, did not differ between benign and malignant human prostate cells. Transport assays demonstrated that CaP cell lines have a higher capacity to transport fructose compared to benign cell lines. However, glucose uptake was not altered between benign and malignant human prostate cell lines. ATP levels in CaP cells were similar in the presence of fructose or glucose. Fructose, but not glucose, significantly altered mRNA expression of HK2, KHK-C, PKM2, and LDH-A in malignant human prostate cells. Taken together, our results suggest that fructose may represent an alternative energy source and may reprogram hexose metabolism in CaP cells. Citation Format: Daniela Carreño, Nestor Corro, Marcia Arredondo, Carmen Navarro, Verónica Torres, Viviana Montecinos, Paula Sotomayor, Francisco Nualart, Julio Cesar Cárdenas, Alejandro S. Godoy. Role of fructose in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 448. doi:10.1158/1538-7445.AM2017-448

BACKGROUND:Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown.METHODS:Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2α knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student's T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival.RESULTS:Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2α is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERα) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated α-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset.CONCLUSIONS:Taking together, these results suggest that HDAC1 and HDAC6 may play a role in ccRCC biology and could represent rational therapeutic targets.

Tumor angiogenesis is widely recognized as one of the “hallmarks of cancer”. Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic therapy escape: (1) upregulation of compensatory/alternative pathways for angiogenesis; (2) vasculogenic mimicry; and (3) vessel co-option. We suggest that an understanding of how a cancer cell adapts to antiangiogenic therapy may also parallel the mechanisms employed in the bourgeoning tumor and isolated metastatic cells delivering responsible for residual disease. Finally, we speculate on strategies to adapt antiangiogenic therapy for future clinical uses.