Hypoxia theranostics of a human prostate cancer xenograft and the resulting effects on the tumor microenvironment (original) (raw)
Related papers
The hypoxic response of tumors is dependent on their microenvironment
Cancer Cell, 2003
To reveal the functional significance of hypoxia and angiogenesis in astrocytoma progression, we created genetically engineered transformed astrocytes from murine primary astrocytes and deleted the hypoxia-responsive transcription factor HIF-1� or its target gene, the angiogenic factor VEGF. Growth of HIF-1�-and VEGF-deficient transformed astrocytes in the vessel-poor subcutaneous environment results in severe necrosis, reduced growth, and vessel density, whereas when the same cells are placed in the vascular-rich brain parenchyma, the growth of HIF-1� knockout, but not VEGF knockout tumors, is reversed: tumors deficient in HIF-1� grow faster, and penetrate the brain more rapidly and extensively. These results demonstrate that HIF-1� has differential roles in tumor progression, which are greatly dependent on the extant microenvironment of the tumor.
The Role of Hypoxia-Induced Factors in Tumor Progression
The Oncologist, 2004
Hypoxia is a common characteristic of locally advanced solid tumors that has been associated with diminished therapeutic response and, more recently, with malignant progression, that is, an increasing probability of recurrence, locoregional spread, and distant metastasis. Emerging evidence indicates that the effect of hypoxia on malignant progression is mediated by a series of hypoxiainduced proteomic and genomic changes activating angiogenesis, anaerobic metabolism, and other processes that enable tumor cells to survive or escape their oxygen-deficient environment. The transcription factor hypoxiainducible factor 1 (HIF-1) is a major regulator of tumor cell adaptation to hypoxic stress. Tumor cells with proteomic and genomic changes favoring survival under hypoxic conditions will proliferate, thereby further aggravating the hypoxia. The selection and expansion of new (and more aggressive) clones, which eventually become the dominant tumor cell type, lead to the establishment of a vicious circle of hypoxia and malignant progression.
Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter
Cancers, 2021
Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tum...
Role of hypoxia in cancer therapy by regulating the tumor microenvironment
Molecular Cancer, 2019
AimClinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy.MethodsRelevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms.ResultsRecent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux.ConclusionHypoxia targeting might be relevant to overcome hypoxia-associated resist...
Contemporary oncology (Poznan, Poland), 2018
Hypoxia characterizes growing tumors and contributes significantly to their aggressiveness. Hypoxia-inducible factors (HIFs 1 and 2) are stabilized and act differentially as transcription factors on tumor growth and are responsible for important cancer hallmarks such as pathologic angiogenesis, cellular proliferation, apoptosis, differentiation and genetic instability as well as affecting tumor metabolism, tumor immune responses, invasion and metastasis. Taking into account the tumor tissue as a whole and considering the interplay of the various partners which react with hypoxia in the tumor site lead to reconsideration of the treatment strategies. Key limitations of treatment success result from the adaptation to the hypoxic milieu sustained by tumor anarchic angiogenesis. This raises immune tolerance by influencing the recruitment of immunosuppressive cells as bone marrow derived suppressor cells (MDSC) or by impairing the infiltration and killing of tumor cells by cytotoxic cells...
Oncotarget
Tumor hypoxia promotes neoangiogenesis and contributes to the radio-and chemotherapy resistant and aggressive phenotype of cancer cells. However, the migratory response of tumor cells and the role of small GTPases regulating the organization of cytoskeleton under hypoxic conditions have yet to be established. Accordingly, we measured the proliferation, migration, RhoA activation, the mRNA and protein levels of hypoxia inducible factor-1alpha (HIF-1α) and three small G-proteins, Rac1, cdc42 and RhoA in a panel of five human tumor cell lines under normoxic and hypoxic conditions. Importantly, HT168-M1 human melanoma cells with high baseline migration capacity showed increased HIF-1α and small GTPases expression, RhoA activation and migration under hypoxia. These activities were blocked by anti-HIF-1α shRNA. Moreover, the in vivo metastatic potential was promoted by hypoxia mimicking CoCl 2 treatment and reduced upon inhibition of HIF-1α in a spleen to liver colonization experiment. In contrast, HT29 human colon cancer cells with low migration capacity showed limited response to in vitro hypoxia. The expression of the small G-proteins decreased both at mRNA and protein levels and the RhoA activation was reduced. Nevertheless, the number of lung or liver metastatic colonies disseminating from orthotopic HT29 grafts did not change upon CoCl 2 or chetomin treatment. Our data demonstrates that the hypoxic environment induces cell-type dependent changes in the levels and activation of small GTPases and results in varying migratory and metastasis promoting responses in different human tumor cell lines.
Tumor hypoxia and heterogeneity: Challenges and opportunities for the future
Seminars in Radiation Oncology, 1996
Many human tumors contain a significant fraction of hypoxic cells that can directly affect responsiveness to therapy. Evidence is increasing that hypoxia may also contribute to malignant progression through effects on signal transduction pathways and regulation of transcription of various genes. New methods for detecting and mapping tumor hypoxia are being applied to directly assess the significance of hypoxia in relation to biological characteristics and responsiveness to therapy. Knowledge of which tumors are hypoxic is being used to test new therapies to exploit hypoxia, such as with new bioreductive drugs that are selectively cytotoxic in hypoxic environments. Recent advances in fundamental research are showing mechanisms and intracellular pathways involved in regulating cellular responses to hy-poxia and reoxygenation. Response to hypoxic stress involves altering the expression of specific genes. Several different classes of hypoxic stress proteins have been identified. These include glucose regulated proteins that function as "chaperones" in protein processing, glycolytic enzymes that maintain energy metabolism under anerobic conditions, proteins involved in oxidative stress responses and maintaining redox homeostasis, various transcription factors, including protooncogenes and suppressor genes, and molecules involved in the regulation of growth signal transduction pathways. There are many challenges and opportunities for basic research and translational research to apply this fundamental knowledge to the clinic.
Cancer Research, 2006
Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O 2 diffusion-limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO 2 within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxygenation not only rendered them resistant to proapoptotic stresses, including serum deprivation and radiotherapy, but also increased their capacity to migrate and organize in tubes. By contrast, prolonged hypoxia failed to exert protective effects and even seemed deleterious when combined with radiotherapy. The use of hypoxia-inducible factor-1A (HIF-1A)-targeting small interfering RNA led us to document that the accumulation of HIF-1A during intermittent hypoxia accounted for the higher resistance of endothelial cells. We also used an in vivo approach to enforce intermittent hypoxia in tumor-bearing mice and found that it was associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (versus normoxia or prolonged hypoxia). Radioresistance was further ascertained by an increased rate of tumor regrowth in irradiated mice preexposed to intermittent hypoxia and confirmed in vitro using distinctly radiosensitive tumor cell lines. In conclusion, we have documented that intermittent hypoxia may condition endothelial cells and tumor cells in such a way that they are more resistant to apoptosis and more prone to participate in tumor progression. Our observations also underscore the potential of drugs targeting HIF-1A to resensitize the tumor vasculature to anticancer treatments.
Oncotarget, 2017
Tumor hypoxia promotes neoangiogenesis and contributes to the radio-and chemotherapy resistant and aggressive phenotype of cancer cells. However, the migratory response of tumor cells and the role of small GTPases regulating the organization of cytoskeleton under hypoxic conditions have yet to be established. Accordingly, we measured the proliferation, migration, RhoA activation, the mRNA and protein levels of hypoxia inducible factor-1alpha (HIF-1α) and three small G-proteins, Rac1, cdc42 and RhoA in a panel of five human tumor cell lines under normoxic and hypoxic conditions. Importantly, HT168-M1 human melanoma cells with high baseline migration capacity showed increased HIF-1α and small GTPases expression, RhoA activation and migration under hypoxia. These activities were blocked by anti-HIF-1α shRNA. Moreover, the in vivo metastatic potential was promoted by hypoxia mimicking CoCl 2 treatment and reduced upon inhibition of HIF-1α in a spleen to liver colonization experiment. In contrast, HT29 human colon cancer cells with low migration capacity showed limited response to in vitro hypoxia. The expression of the small G-proteins decreased both at mRNA and protein levels and the RhoA activation was reduced. Nevertheless, the number of lung or liver metastatic colonies disseminating from orthotopic HT29 grafts did not change upon CoCl 2 or chetomin treatment. Our data demonstrates that the hypoxic environment induces cell-type dependent changes in the levels and activation of small GTPases and results in varying migratory and metastasis promoting responses in different human tumor cell lines.
Roles of hypoxia in tumor progression and novel strategies for cancer treatment
Biomedical Research and Therapy
The metabolic process of normal cells in general and of cancer cells in particular requires an important molecule-oxygen. In tumors, the oxygen level tends to decrease gradually from the outer layers to the central core, leading to a condition termed``hypoxia. '' Changes in the oxygen level modify the signaling pathways and metabolic activities of cancer cells. Basically, tumor development is divided into three stages: initiation, promotion, and progression. Among them, the effects of hypoxia are most evident during tumor progression. In this review, we summarize previous findings on the mechanisms underlying hypoxia-induced alterations in the expression of genes and proteins associated with hypoxia-inducible factors (HIFs), which play a central role in the development of malignancy in many types of cancer. We also present the latest evidence on HIF-targeted cancer treatment that yields positive outcomes in vitro and in vivo.