The Allosteric Hemoglobin Effector ITPP Inhibits Metastatic Colon Cancer in Mice

Limani, Përparim; Linecker, Michael; Schneider, Marcel; Kron, Philipp; Tschuor, Christoph; Kachaylo, Ekaterina; Ungethuem, Udo; Nicolau, Claude; Lehn, Jean‐Maríe; Graf, Rolf; Humar, Bostjan; Clavien, Pierre‐Alain

doi:10.1097/sla.0000000000002431

Cited by 10 publications

(13 citation statements)

References 32 publications

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“…Although this mechanism is attractive, it remains to be seen whether this is a general process that is relevant within the context of CRC. One mechanism in favor of a process linking hypoxia and OPN is provided by a recent paper [123]. It was reported that the restoration of oxygen in metastatic colon cancer through Myo-Inositoltrispyrophosphate (ITPP), a nontoxic, anti-hypoxic molecule that recently has shown significant benefits in experimental cancer models, particularly when combined with standard chemotherapy, inhibits tumor spread and is accompanied by a reduction in malignant serum markers including osteopontin, leading to markedly improved animal survival.…”

Section: Metastasis Formationmentioning

confidence: 99%

Osteopontin as a Regulator of Colorectal Cancer Progression and Its Clinical Applications

Amilca-Seba

Sabbah

Larsen

et al. 2021

Cancers

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A high expression of the phosphoprotein osteopontin (OPN) has been associated with cancer progression in several tumor types, including breast cancer, hepatocarcinoma, ovarian cancer, and colorectal cancer (CRC). Interestingly, OPN is overexpressed in CRC and is associated with a poor prognosis linked to invasion and metastasis. Here, we review the regulation and functions of OPN with an emphasis on CRC. We examine how epigenetic and genetic regulators interact with the key signaling pathways involved in this disease. Then, we describe the role of OPN in cancer progression, including proliferation, survival, migration, invasion, and angiogenesis. Furthermore, we outline the interest of using OPN as a clinical biomarker, and discuss if and how osteopontin can be implemented as a routine assay in clinical laboratories for monitoring CRC patients. Finally, we discuss the use of OPN an attractive, but challenging, therapeutic target.

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Section: Metastasis Formationmentioning

confidence: 99%

Osteopontin as a Regulator of Colorectal Cancer Progression and Its Clinical Applications

Amilca-Seba

Sabbah

Larsen

et al. 2021

Cancers

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“…The allosteric effector of hemoglobin myo-inositol trispyrophosphate (ITPP) was also shown to locally increase the pO 2 in hypoxic tumors. Even though mixed results exists on the potency of ITPP, which is primarily due to pharmacokinetic aspects, we and others demonstrated its chemo- and radiosensitization capacity in both immunocompromised and immunocompetent tumor models [ 349 – 352 ], For a more comprehensive review on the topic, see [ 348 ].…”

Section: Radiotherapy and Tumor Hypoxiamentioning

confidence: 99%

Interfering with Tumor Hypoxia for Radiotherapy Optimization

Telarovic

Wenger

Pruschy

2021

J Exp Clin Cancer Res

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Hypoxia in solid tumors is an important predictor of treatment resistance and poor clinical outcome. The significance of hypoxia in the development of resistance to radiotherapy has been recognized for decades and the search for hypoxia-targeting, radiosensitizing agents continues. This review summarizes the main hypoxia-related processes relevant for radiotherapy on the subcellular, cellular and tissue level and discusses the significance of hypoxia in radiation oncology, especially with regard to the current shift towards hypofractionated treatment regimens. Furthermore, we discuss the strategies to interfere with hypoxia for radiotherapy optimization, and we highlight novel insights into the molecular pathways involved in hypoxia that might be utilized to increase the efficacy of radiotherapy.

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“…Murine brain (MBrMEC) and bone marrow (MBMMEC)-derived organospecific microvascular endothelial cells (ECs) were established as described 34,[36][37][38] and patented (N1170 3915.6, N13/521715). EL4 (ATCC ® TIB-39™) and EL4-IL2 (ATCC ® TIB-181™) were purchased from ATCC.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…28,30 This tumour suppressor molecule is a primary regulator of vessel formation and modulates endothelial cell reactivity through the control of immune checkpoints, such as PD-L1, 31 through cross controlling NOTCH4. 32 Myo-inositol-trispyrophosphate is a non-cytotoxic molecule, 28,33 and its tumour-reducing effects 30,34 are suggested to operate through vessel normalization, leading to sustained increases in oxygen partial pressure (pO 2 ) which counteracts hypoxia inside the tumour and inverts its effects. This work shows that ITPP-induced stable normalization induces deep changes in the tumour microenvironment due to hypoxia compensation using two tumour models: melanoma and mammary carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Tumour angiogenesis normalized by myo‐inositol trispyrophosphate alleviates hypoxia in the microenvironment and promotes antitumor immune response

Hafny‐Rahbi

Brodaczewska²,

Collet

et al. 2021

J Cellular Molecular Medi

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Pathologic angiogenesis directly responds to tumour hypoxia and controls the molecular/cellular composition of the tumour microenvironment, increasing both immune tolerance and stromal cooperation with tumour growth. Myo‐inositol‐trispyrophosphate (ITPP) provides a means to achieve stable normalization of angiogenesis. ITPP increases intratumour oxygen tension (pO2) and stabilizes vessel normalization through activation of endothelial Phosphatase‐and‐Tensin‐homologue (PTEN). Here, we show that the tumour reduction due to the ITPP‐induced modification of the tumour microenvironment by elevating pO2 affects the phenotype and properties of the immune infiltrate. Our main observations are as follows: a relative change in the M1 and M2 macrophage‐type proportions, increased proportions of NK and CD8+T cells, and a reduction in Tregs and Th2 cells. We also found, in vivo and in vitro, that the impaired access of PD1+NK cells to tumour cells is due to their adhesion to PD‐L1+/PD‐L2+ endothelial cells in hypoxia. ITPP treatment strongly reduced PD‐L1/PD‐L2 expression on CD45+/CD31+ cells, and PD1+ cells were more numerous in the tumour mass. CTLA‐4+ cell numbers were stable, but level of expression decreased. Similarly, CD47+ cells and expression were reduced. Consequently, angiogenesis normalization induced by ITPP is the mean to revert immunosuppression into an antitumor immune response. This brings a key adjuvant effect to improve the efficacy of chemo/radio/immunotherapeutic strategies for cancer treatment.

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The Allosteric Hemoglobin Effector ITPP Inhibits Metastatic Colon Cancer in Mice

Cited by 10 publications

References 32 publications

Osteopontin as a Regulator of Colorectal Cancer Progression and Its Clinical Applications

Osteopontin as a Regulator of Colorectal Cancer Progression and Its Clinical Applications

Interfering with Tumor Hypoxia for Radiotherapy Optimization

Tumour angiogenesis normalized by myo‐inositol trispyrophosphate alleviates hypoxia in the microenvironment and promotes antitumor immune response

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