CD46 Expression is an Unfavorable Prognostic Factor in Breast Cancer Cases

Maciejczyk, Adam; Szelachowska, Jolanta; Szynglarewicz, B.; Szulc, R.; Szulc, Agata; Wysocka, Teresa; Jagoda, Ewa; Lage, Hermann; Surowiak, Paweł

doi:10.1097/pai.0b013e31821a0be9

Cited by 41 publications

(43 citation statements)

References 8 publications

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“…CD46 has been implicated in the development and progression of several cancer types. Elevated expression of CD46 has been observed in medulloblastomas, breast cancers, and CRCs [30–32]. Although the expression level of CD46 was significantly higher in CRC tissues compared with the adjacent normal colon tissues, CD46 expression was not associated with colon cancer progression [31].…”

Section: Resultsmentioning

confidence: 99%

“…It has also been demonstrated that CD46 is implicated in the development and progression of several cancers. CD46 expression is elevated in medulloblastoma [32], while CD46 expression has been linked with poor prognosis in breast cancer [30]. It has been proposed that overexpression of CD46 may serve to protect cancer cells from complement-dependent cytotoxicity, thereby evading destruction caused by the immune system [36, 37].…”

Section: Discussionmentioning

confidence: 99%

“…Expression of CD46 also represents an independent risk factor for disease-free survival and overall survival, demonstrating that patients with tumors negative for CD46 have an increased progression-free time and overall survival time as compared with patients with CD46-positive tumors. A study demonstrates that breast cancers manifest CD46 expression and that it is linked to a less favorable prognosis [30]. …”

Section: Discussionmentioning

confidence: 99%

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Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers

Cho

Kwon

et al. 2016

Oncotarget

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CD46 is a complement inhibitor membrane cofactor which also acts as a receptor for various microbes, including species B adenoviruses (Ads). While most Ad gene therapy vectors are derived from species C and infect cells through coxsackie-adenovirus receptor (CAR), CAR expression is downregulated in many cancer cells, resulting inefficient Ad-based therapeutics. Despite a limited knowledge on the expression status of many cancer cells, an increasing number of cancer gene therapy studies include fiber-modified Ad vectors redirected to the more ubiquitously expressed CD46. Since our finding from tumor microarray indicate that CD46 was overexpressed in cancers of the prostate and colon, fiber chimeric Ad5/35 vectors that have infection tropism for CD46 were employed to demonstrate its efficacy in colorectal cancers (CRC). CD46-overexpressed cells showed a significantly higher response to Ad5/35-GFP and to Ad5/35-tk/GCV. While CRC cells express variable levels of CD46, CD46 expression was positively correlated with Ad5/35-mediated GFP fluorescence and accordingly its cell killing. Injection of Ad5/35-tk/GCV caused much greater tumor-suppression in mice bearing CD46-overexpressed cancer xenograft compared to mock group. Analysis of CRC samples revealed that patients with positive CD46 expression had a higher survival rate (p=0.031), carried tumors that were well-differentiated, but less invasive and metastatic, and with a low T stage (all p<0.05). Taken together, our study demonstrated that species B-based adenoviral gene therapy is a suitable approach for generally CD46-overexpressed CRC but would require careful consideration preceding CD46 analysis and categorizing CRC patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers

Cho

Kwon

et al. 2016

Oncotarget

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“…It is intriguing but not fully understood why prostate cancer expresses high levels of CD46. It is tempting to hypothesize that tumor cells need to evade the host immune system, innate or adaptive, and CD46 forms part of the defense shield that the tumor uses to evade immune surveillance (51)(52)(53). That being said, it is also possible that CD46 performs other functions that are critical for tumor cell invasion, survival, or self-renewal.…”

Section: Discussionmentioning

confidence: 99%

Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer

Su¹,

Liu²,

Behrens³

et al. 2018

JCI Insight

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Although initially responsive to androgen signaling inhibitors (ASIs), metastatic castration-resistant prostate cancer (mCRPC) inevitably develops and is incurable. In addition to adenocarcinoma (adeno), neuroendocrine prostate cancer (NEPC) emerges to confer ASI resistance. We have previously combined laser capture microdissection and phage antibody display library selection on human cancer specimens and identified novel internalizing antibodies binding to tumor cells residing in their tissue microenvironment. We identified the target antigen for one of these antibodies as CD46, a multifunctional protein that is best known for negatively regulating the innate immune system. CD46 is overexpressed in primary tumor tissue and CRPC (localized and metastatic; adeno and NEPC), but expressed at low levels on normal tissues except for placental trophoblasts and prostate epithelium. Abiraterone- and enzalutamide-treated mCRPC cells upregulate cell surface CD46 expression. Genomic analysis showed that the CD46 gene is gained in 45% abiraterone-resistant mCRPC patients. We conjugated a tubulin inhibitor to our macropinocytosing anti-CD46 antibody and showed that the resulting antibody-drug conjugate (ADC) potently and selectively kills both adeno and NEPC cell lines in vitro (sub-nM EC50) but not normal cells. CD46 ADC regressed and eliminated an mCRPC cell line xenograft in vivo in both subcutaneous and intrafemoral models. Exploratory toxicology studies of the CD46 ADC in non-human primates demonstrated an acceptable safety profile. Thus, CD46 is an excellent target for antibody-based therapy development, which has potential to be applicable to both adenocarcinoma and neuroendocrine types of mCRPC that are resistant to current treatment.

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“…12 The surface of a cancer cell often overexpresses certain transmembrane proteins that serve as receptors for viruses. Metastatic cancer cells usually overexpress sialic acid residues, 13 CD46, 14 , 15 and nectin 4, 16 , 17 molecules that are located on their surface and can serve as receptors for oncolytic paramyxoviruses. 18–20 Cancer cells are commonly defective for type 1 IFN induction and response to IFN treatment.…”

Section: Figurementioning

confidence: 99%

Oncolysis by paramyxoviruses: preclinical and clinical studies

Matveeva

Guo

Senin

et al. 2015

Molecular Therapy - Oncolytics

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Preclinical studies demonstrate that a broad spectrum of human malignant cells can be killed by oncolytic paramyxoviruses, which include cells of ecto-, endo-, and mesodermal origin. In clinical trials, significant reduction in size or even complete elimination of primary tumors and established metastases are reported. Different routes of viral administration (intratumoral, intravenous, intradermal, intraperitoneal, or intrapleural), and single- versus multiple-dose administration schemes have been explored. The reported side effects are grade 1 and 2, with the most common among them being mild fever. Some advantages in using para-myxoviruses as oncolytic agents versus representatives of other viral families exist. The cytoplasmic replication results in a lack of host genome integration and recombination, which makes paramyxoviruses safer and more attractive candidates for widely used therapeutic oncolysis in comparison with retroviruses or some DNA viruses. The list of oncolytic paramyxovirus representatives includes attenuated measles virus (MV), mumps virus (MuV), low pathogenic Newcastle disease (NDV), and Sendai (SeV) viruses. Metastatic cancer cells frequently overexpress on their surface some molecules that can serve as receptors for MV, MuV, NDV, and SeV. This promotes specific viral attachment to the malignant cell, which is frequently followed by specific viral replication. The paramyxoviruses are capable of inducing efficient syncytium-mediated lyses of cancer cells and elicit strong immunomodulatory effects that dramatically enforce anticancer immune surveillance. In general, preclinical studies and phase 1–3 clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches.

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CD46 Expression is an Unfavorable Prognostic Factor in Breast Cancer Cases

Cited by 41 publications

References 8 publications

Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers

Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers

Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer

Oncolysis by paramyxoviruses: preclinical and clinical studies

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