Development of conformational antibodies targeting Cripto-1 with neutralizing effects in vitro

Focà, Giuseppina; Iaccarino, Emanuela; Focà, Annalia; Sanguigno, Luca; Untiveros, Gustavo; Cuevas‐Nunez, Maria; Strizzi, Luigi; Leonardi, Antonio; Ruvo, Menotti; Sandomenico, Annamaria

doi:10.1016/j.biochi.2019.01.016

Cited by 16 publications

(17 citation statements)

References 72 publications

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“…CRIPTO has also been reported as a functional cancer stem cell marker in head and neck cancers and, more recently, in esophageal squamous cell carcinoma, hepatocellular carcinoma, and post-therapy, recurrent osteotropic prostate cancer [21,22]. Several groups are seeking to develop CRIPTO as a biomarker of tumor aggressiveness and validate therapeutic modalities directed at blocking CRIPTO-induced oncogenesis [19,[23][24][25].…”

Section: Introductionmentioning

confidence: 99%

CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress

et al. 2020

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Background CRIPTO is a multi-functional signaling protein that promotes stemness and oncogenesis. We previously developed a CRIPTO antagonist, ALK4L75A-Fc, and showed that it causes loss of the stem cell phenotype in normal mammary epithelia suggesting it may similarly inhibit CRIPTO-dependent plasticity in breast cancer cells. Methods We focused on two triple negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to measure the effects of ALK4L75A-Fc on cancer cell behavior under nutrient deprivation and endoplasmic reticulum stress. We characterized the proliferation and migration of these cells in vitro using time-lapse microscopy and characterized stress-dependent changes in the levels and distribution of CRIPTO signaling mediators and cancer stem cell markers. We also assessed the effects of ALK4L75A-Fc on proliferation, EMT, and stem cell markers in vivo as well as on tumor growth and metastasis using inducible lentiviral delivery or systemic administration of purified ALK4L75A-Fc, which represents a candidate therapeutic approach. Results ALK4L75A-Fc inhibited adaptive responses of breast cancer cells under conditions of nutrient and ER stress and reduced their proliferation, migration, clonogenicity, and expression of EMT and cancer stem cell markers. ALK4L75A-Fc also inhibited proliferation of human breast cancer cells in stressed tumor microenvironments in xenografts and reduced both primary tumor size and metastatic burden. Conclusions Cancer cell adaptation to stresses such as nutrient deprivation, hypoxia, and chemotherapy can critically contribute to dormancy, metastasis, therapy resistance, and recurrence. Identifying mechanisms that govern cellular adaptation, plasticity, and the emergence of stem-like cancer cells may be key to effective anticancer therapies. Results presented here indicate that targeting CRIPTO with ALK4L75A-Fc may have potential as such a therapy since it inhibits breast cancer cell adaptation to microenvironmental challenges and associated stem-like and EMT phenotypes.

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Section: Introductionmentioning

confidence: 99%

CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress

et al. 2020

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“…Especially Ab19917 from Abcam reacted strongly to geltrex (Figure 2). One way forward is to generate monoclonal cripto-1 antibodies such as has been done recently by Foca et al, 66 which designed a cripto-1 antibody against the CFC domain. Ab19917 is polyclonal and produced with an immunogen that includes both the EGF and CFC domain, greatly increasing its chances of cross-reactivity.…”

Section: Discussionmentioning

confidence: 99%

An evaluation of different Cripto‐1 antibodies and their variable results

Gudbergsson

Duroux

2019

J of Cellular Biochemistry

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Cripto‐1 is a protein expressed during embryonal development and has been linked to several malignant processes in cancer. Since the discovery of cripto‐1 in the late 1980s, it has become a subject of biomarker investigation in several types of cancer which in many cases relies on immunolocalization of cripto‐1 using antibodies. Investigating cripto‐1 expression and localization in primary glioblastoma cells, we discovered nonspecific binding of cripto‐1 antibody to the extracellular matrix Geltrex. A panel of four cripto‐1 antibodies was investigated with respect to their binding to the Geltrex matrix and to the cripto‐1 positive control cells NTERA2. The cripto‐1 expression was varied for the different antibodies with respect to cellular localization and fixation methods. To further elaborate on these findings, we present a systematic review of cripto‐1 antibodies found in the literature and highlight some possible cross reactants with data on sequence alignments and structural comparison of EGF domains.

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“…Cripto-1 has been demonstrated to mechanistically contribute to metastasis, recurrence, and drug resistance [23,46,118,119]. Cripto-1 is a promising immunotherapeutic target in hepatocellular carcinoma, glioma, melanoma, prostate cancer, and metastatic breast cancer [37,38,47,52,120,121].…”

Section: Role Of Cripto-1 In Metastasis and Recurrencementioning

confidence: 99%

Cripto-1 as a Potential Target of Cancer Stem Cells for Immunotherapy

Ishii¹,

Afify

Hassan

et al. 2021

Cancers

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The immune system has been found to be suppressed in cancer patients. Cancer cells are extremely resistant to chemotherapeutic drugs, conventional immunotherapy, or cancer antigen vaccine therapy. Cancer immunotherapy, which is mainly based on immune checkpoint inhibitors, such as those for PD-1, PD-L1, and CTLA4, is an effective treatment method. However, no immunotherapeutic target has been found that retains validity in the face of tumor diversity. The transforming growth factor (TGF)-β cytokine family possesses broad biological activity and is involved in the induction and/or transdifferentiation of helper T cells, which are important in immunotherapy. Nodal is a member of the TGF-β family playing important roles in tissue stem cells and cancer stem cells (CSCs), interacting with the co-receptor Cripto-1, as well as with Activin type IB (Alk4) and Activin typeIIreceptors, and maintaining stemness and Notch and Wnt/β-catenin signaling in CSCs. In recent years, it has been reported that Cripto-1 could be a potential therapeutic target in CSCs. Here, we review the accumulated literature on the molecular mechanisms by which Cripto-1 functions in CSCs and discuss the potential of Cripto-1 as an immunotherapeutic target in CSCs.

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Development of conformational antibodies targeting Cripto-1 with neutralizing effects in vitro

Cited by 16 publications

References 72 publications

CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress

CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress

An evaluation of different Cripto‐1 antibodies and their variable results

Cripto-1 as a Potential Target of Cancer Stem Cells for Immunotherapy

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