Hypoxic control of metastasis Rankin, Erinn B.; Giaccia, Amato J.
Science (American Association for the Advancement of Science),
04/2016, Letnik:
352, Številka:
6282
Journal Article
Recenzirano
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Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor ...promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease.
Low oxygen tension (hypoxia) is a hallmark of cancer that influences cancer cell function, but is also an important component of the tumour microenvironment as it alters the extracellular matrix, ...modulates the tumour immune response and increases angiogenesis. Here we discuss the regulation and role of hypoxia and its key transcriptional mediators, the hypoxia-inducible factor (HIF) family of transcription factors, in the tumour microenvironment and stromal compartments.
The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, ...stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed within cellular components of the tumor microenvironment where AXL signaling contributes to the immunosuppressive and protumorigenic phenotypes. A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. Here we review the literature that has illuminated the cellular and molecular mechanisms by which AXL signaling promotes tumor progression and we will discuss the therapeutic potential of AXL inhibition for cancer therapy.
Osteoblasts are an important component of the hematopoietic microenvironment in bone. However, the mechanisms by which osteoblasts control hematopoiesis remain unknown. We show that augmented HIF ...signaling in osteoprogenitors results in HSC niche expansion associated with selective expansion of the erythroid lineage. Increased red blood cell production occurred in an EPO-dependent manner with increased EPO expression in bone and suppressed EPO expression in the kidney. In contrast, inactivation of HIF in osteoprogenitors reduced EPO expression in bone. Importantly, augmented HIF activity in osteoprogenitors protected mice from stress-induced anemia. Pharmacologic or genetic inhibition of prolyl hydroxylases1/2/3 in osteoprogenitors elevated EPO expression in bone and increased hematocrit. These data reveal an unexpected role for osteoblasts in the production of EPO and modulation of erythropoiesis. Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment.
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► Osteoblasts produce EPO through a HIF-dependent mechanism ► Modulation of PHD/VHL/HIF signaling in osteoblasts induces EPO and protects from anemia ► Augmented HIF activity in osteoblasts expands the HSC niche in the bone marrow
HIF signaling modulates erytropoeitin production by osteoblasts, increasing the numbers of erythroid progenitors in the hematopoietic microenvironment in bone and presenting a potential therapeutic target for the treatment of anemia.
It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before ...metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.
Unique features of tumours that can be exploited by targeted therapies are a key focus of current cancer research. One such approach is known as synthetic lethality screening, which involves ...searching for genetic interactions of two mutations whereby the presence of either mutation alone has no effect on cell viability but the combination of the two mutations results in cell death. The presence of one of these mutations in cancer cells but not in normal cells can therefore create opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy. Here, we summarize strategies that can be used to identify synthetic lethal interactions for anticancer drug discovery, describe examples of such interactions that are currently being investigated in preclinical and clinical studies of targeted anticancer therapies, and discuss the challenges of realizing the full potential of such therapies.
Metastasis, the leading cause of cancer deaths, is an intricate process involving many important tumor and stromal proteins that have yet to be fully defined. This review discusses critical ...components necessary for the metastatic cascade, including hypoxia, inflammation, and the tumor microenvironment. More specifically, this review focuses on tumor cell and stroma interactions, which allow cell detachment from a primary tumor, intravasation to the blood stream, and extravasation at a distant site where cells can seed and tumor metastases can form. Central players involved in this process and discussed in this review include integrins, matrix metalloproteinases, and soluble growth factors/matrix proteins, including the connective tissue growth factor and lysyl oxidase.
Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore ...significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells’ demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine’s complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy.
Autophagy is a cellular degradation process in which portions of the cell's cytoplasm and organelles are sequestered in a double-membrane bound vesicle called an autophagosome. Fusion of ...autophagosomes with lysosomes results in the formation of autolysosomes, where the proteins and organelles are degraded. This degradation pathway is induced under nutrient deprivation, metabolic stress or microenvironmental conditions to ensure energy balance, clearance of damaged proteins and adaptation to stress. Disruption of autophagy is involved in diverse human diseases including cancer. In particular, the regulation of autophagy in cancer cells is complex since it can enhance tumor cell survival in response to certain stresses, yet it can also act to suppress the initiation of tumor growth. Understanding the signaling pathways involved in the regulation of autophagy as well as the autophagy process itself represents new directions in the development of anticancer therapies. In this review, we discuss recent advances in our understanding the complexity of the autophagy process and the development of targeted therapies that modulate autophagy in cancer cells in the clinic.
Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), ...frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1α, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1α suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1α expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1α exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1α expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1α recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1α expression as a therapeutic modality for the treatment of ccRCC.
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•PGC-1α suppression reprograms mitochondrial metabolism in ccRCC•PGC-1α repression is HIF dependent and requires induction of the HIF target gene Dec1•PGC-1α expression induces oxidative stress and suppresses ccRCC tumor growth•Low PGC-1α expression is a marker of poor prognosis in ccRCC
LaGory et al. show that PGC-1α expression is suppressed in ccRCC in a HIF-α- and Dec1-dependent manner. Rescued expression of PGC-1α restores mitochondrial function, induces oxidative stress, and suppresses tumor growth. In patients, low expression of PGC-1α is associated with poor overall survival and advanced-stage metastatic disease.
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