Anti-VEGF antibody therapy induces tumor hypoxia and stanniocalcin 2 expression and potentiates growth of human colon cancer xenografts

Miyazaki, Shôzo; Kikuchi, Hirotoshi; Iino, Ichirota; Uehara, Takashi; Setoguchi, Tomohiko; Fujita, Takeshi; Hiramatsu, Yoshihiro; Ohta, Michio; Kamiya, Kinji; Kitagawa, Kyoko; Kitagawa, Masatoshi; Baba, Satoshi; Konno, Hiroyuki

doi:10.1002/ijc.28686

Cited by 52 publications

(50 citation statements)

References 42 publications

(57 reference statements)

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“…To achieve this, we analyzed tissue from KIC mice that had been treated with the VEGF inhibitor mouse chimeric r84 (mcr84) (49). The rationale behind this approach is that anti-angiogenic therapy increases intratumoral hypoxia (5,50). Using these mice, we have confirmed previously that treatment with mcr84 induces hypoxia in tumors compared with untreated tumors as seen by pimonidazole staining (5).…”

Section: Fbln5 Expression In Pancreaticmentioning

confidence: 84%

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Topalovski¹,

Hagopian²,

Wang

et al. 2016

Journal of Biological Chemistry

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The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of ␣5␤1 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECMdriven reactive oxygen species production and supports PDA progression. Compared with normal pancreatic tissue, Fbln5 is expressed abundantly in the stroma of PDA; however, the mechanisms underlying the stimulation of Fbln5 expression in PDA are undefined. Using in vitro and in vivo approaches, we report that hypoxia triggers Fbln5 expression in a TGF-␤-and PI3K-dependent manner. Pharmacologic inhibition of TGF-␤ receptor, PI3K, or protein kinase B (AKT) was found to block hypoxia-induced Fbln5 expression in mouse embryonic fibroblasts and 3T3 fibroblasts. Moreover, tumor-associated fibroblasts from mouse PDA were also responsive to TGF-␤ receptor and PI3K/AKT inhibition with regard to suppression of Fbln5. In genetically engineered mouse models of PDA, therapy-induced hypoxia elevated Fbln5 expression, whereas pharmacologic inhibition of TGF-␤ signaling reduced Fbln5 expression. These findings offer insight into the signaling axis that induces Fbln5 expression in PDA and a potential strategy to block its production.The maintenance of solid tumors relies heavily on cues received from the surrounding environment. The ECM 2 is composed of structural proteins such as FN and collagen, which promote signaling through integrins and receptor tyrosine kinases (1, 2). ECM signaling is modulated by matricellular proteins, which regulate ECM-cell interactions without serving a direct structural function (3-5). The composition of the ECM is dynamic and varies between tumors and tumor types, contributing to intra-and intertumor heterogeneity, which presents challenges for effective therapeutic strategies. Furthermore, mouse studies have revealed anti-and pro-tumorigenic functions for ECM (5-7). In addition to ECM, stromal cells, including endothelial cells, immune cells, and fibroblasts, are present in the tumor microenvironment. These cells contribute to tumor growth, invasion, and chemoresponse (8 -10).During tumor progression, cancer cells release factors that maintain a microenvironment conducive for growth. For example, TGF-␤ is a cytokine expressed in many cancers that enhances the expression of multiple ECM molecules, including but not limited to FN, collagen, elastin, and fibulins (11-13). Fbln5 is a 448-amino acid secretory glycoprotein of the fibulin family of matricellular proteins. Fbln5 is unique among its members as it contains an RGD-integrin binding domain and can ligate a number of integrins (14). Fbln5 is ex...

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Section: Fbln5 Expression In Pancreaticmentioning

confidence: 84%

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Topalovski¹,

Hagopian²,

Wang

et al. 2016

Journal of Biological Chemistry

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“…For instance, the VEGF‐neutralizing antibody Avastin (bevacizumab) is an approved antiangiogenic cancer therapeutic. However, some reports show that antiangiogenic agents indeed increase tumor invasiveness and metastasis in xenograft models due to increased tumor hypoxia and HIF‐1α expression . These findings emphasize the need to explore the possibilities of targeting HIF‐1 directly to solve the problem of resistance and relapse.…”

Section: Discussionmentioning

confidence: 99%

HIF‐1 at the crossroads of hypoxia, inflammation, and cancer

Balamurugan

2015

Intl Journal of Cancer

462

353

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The complex cross-talk of intricate inter-cellular signaling networks between the tumor and stromal cells promotes cancer progression. Hypoxia is one of the most common conditions encountered within the tumor microenvironment that drives tumor progression. Most responses to hypoxia are elicited by a family of transcription factors called hypoxia-inducible factors (HIFs), which induce expression of a diverse set of genes that assist cells to adapt to hypoxic environments. Among the three HIF protein family members, the role of HIF-1 is well established in cancer progression. HIF-1 functions as a signaling hub to coordinate the activities of many transcription factors and signaling molecules that impact tumorigenesis. This mini review discusses the complex role of HIF-1 and its context-dependent partners under various cancer-promoting events including inflammation and generation of cancer stem cells (CSCs), which are implicated in tumor metastasis and relapse. In addition, the review highlights the importance of therapeutic targeting of HIF-1 for cancer prevention.

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“…STC2 promotes tumorigenicity and accelerates tumor growth in colon cancer. 26 Breast cancer growth is insensitive to progestins, and knockdown of STC1 inhibits proliferation of tumor cells expressing progesterone receptor (PR), suggesting that STC1 may play a potential role in therapy of breast cancer. 27 …”

Section: Proliferationmentioning

confidence: 99%

“…The treatment with anti-STC1 monoclonal antibody or siRNA leads to elevated apoptosis and cell cycle arrest in G0/G1 phase in ovarian carcinoma cells. 26 …”

Section: Cell Apoptosismentioning

confidence: 99%

Evolution and functions of stanniocalcins in cancer

Zhang

et al. 2015

Int J Immunopathol Pharmacol

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Corpuscles of stannius (CS), a small endocrine gland located on the ventral surface of the kidneys of bony fishes, is extracted to purify stanniocalcins (STCs), which inhibit whole-body Ca2+ influx in the whole body, especially in gill and gut. CSs were first considered to be unique endocrine glands in fish, but were further verified to appear in mammalians, indicating that STCs may function in mammalians as calcium regulation, oxidative stress, anti-inflammation, angiogenesis, ischemia reperfusion, etc. Moreover, the relationship and molecular mechanisms of STC1 expression in cancer become the studied focus and front field. STC2 as a STC1 homolog is identified by searching for related sequences in expressed sequence tag databases. Although mammalian STC1 and STC2 are not expressed ubiquitously in tissue cells, they are distributed in a wide variety of tissues and organs including cancer, and play an important role in tumor development and progression. Molecular structureSTC is present in all vertebrates as two isoforms, STC1 and STC2, encoded by separate genes. 1 STC1, originally described as an antihypercalcemic hormone in fish, is highly expressed in differentiated mammalian neurons. STC1 adopts a dimeric and slightly elongated structure with a high content of alpha-helices. 2 STC2, a homolog of STC1, is a 56kD glycoprotein hormone that confers calcitonin-like activity. A widespread distribution of SCT1 and STC2 is present in mammals and fish, in which the highest amount of STC mRNA is in the heart but lower amounts are found in the neural complex, branchial basket, and endostyle. STCs have a conserved pattern of 10 cysteines in Evolution and functions of stanniocalcins in cancer S-J Chu, 1 J Zhang, 2 R Zhang, 2 W-W Lu 2 and J-S Zhu 2 Abstract Stanniocalcin (STC), first isolated from the corpuscles of stannius of teleost fishes, was originally known for its regulation on calcium/phosphate transport. Increasing evidence demonstrates that STCs display the important function in some physiological and pathological behaviors such as calcium regulation, oxidative stress, anti-inflammation, angiogenesis, ischemia reperfusion, nerve diseases, etc. Moreover, STCs are implicated in the development and progression of multiple malignancies through promoting cell growth, proliferation, invasion, metastasis, and apoptotic escape. Some studies have shown that NF-κB upregulates STC expression, thereby activating the downstream HIF-1/ERK1/2 signaling pathway, enhancing the transcriptional activity of tumor-related factors (MMP-2/9, cyclinD1, Bcl-2, N-cadherin, etc) and contributing to tumorigenesis. Here, this brief review describes recent progress of STCs in mammalians, focused mainly on their critical functions in cancer.

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Anti-VEGF antibody therapy induces tumor hypoxia and stanniocalcin 2 expression and potentiates growth of human colon cancer xenografts

Cited by 52 publications

References 42 publications

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

HIF‐1 at the crossroads of hypoxia, inflammation, and cancer

Evolution and functions of stanniocalcins in cancer

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