Expression of CD44v6-Containing Isoforms Influences Cisplatin Response in Gastric Cancer Cells

Pereira, Carla; Ferreira, Daniel; Mendes, Nuno; Granja, Pedro L.; Almeida, Gabriela M.; Oliveira, Carla

doi:10.3390/cancers12040858

Cited by 14 publications

(16 citation statements)

References 41 publications

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“…Table 1 summarizes the data from published studies in which different CD44 isoforms were shown to cooperate with STAT3 in different cancer models. ( 76 – 79 , 81 , 83 , 86 , 87 , 89 – 92 )…”

Section: Cd44 and Stat3 Crosstalk In Cancermentioning

confidence: 99%

CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

Martincuks

Zhao

et al. 2020

Front. Oncol.

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Despite significant progress in cancer therapy over the last decades, ovarian cancer remains the most lethal gynecologic malignancy worldwide with the five-year overall survival rate less than 30% due to frequent disease recurrence and chemoresistance. CD44 is a non-kinase transmembrane receptor that has been linked to cancer metastatic progression, cancer stem cell maintenance, and chemoresistance development via multiple mechanisms across many cancers, including ovarian, and represents a promising therapeutic target for ovarian cancer treatment. Moreover, CD44-mediated signaling interacts with other well-known pro-tumorigenic pathways and oncogenes during cancer development, such as signal transducer and activator of transcription 3 (STAT3). Given that both CD44 and STAT3 are strongly implicated in the metastatic progression and chemoresistance of ovarian tumors, this review summarizes currently available evidence about functional crosstalk between CD44 and STAT3 in human malignancies with an emphasis on ovarian cancer. In addition to the role of tumor cell-intrinsic CD44 and STAT3 interaction in driving cancer progression and metastasis, we discuss how CD44 and STAT3 support the pro-tumorigenic tumor microenvironment and promote tumor angiogenesis, immunosuppression, and cancer metabolic reprogramming in favor of cancer progression. Finally, we review the current state of therapeutic CD44 targeting and propose superior treatment possibilities for ovarian cancer.

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Section: Cd44 and Stat3 Crosstalk In Cancermentioning

confidence: 99%

CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

Martincuks

Zhao

et al. 2020

Front. Oncol.

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“…In the stomach, we have shown that CD44v6 is considerably de novo expressed in gastric pre-malignant and malignant lesions (more than 60% of all GCs), while the normal gastric mucosa remains negative for this marker [ 14 ]. Additionally, we have recently demonstrated that CD44v6 has been correlated with poor prognosis [ 15 ] and aggressive behavior of the disease [ 16 ], suggesting its value not only for early diagnosis but also for prognosis and as a therapeutic target in GC.…”

Section: Introductionmentioning

confidence: 99%

“…Bioorthogonal Michael-addition click chemistry was employed for the site-specific conjugation of CD44v6 half-antibody to maleimide-modified PNPs. Finally, the ability of the CD44v6 half-antibody-conjugated PNPs to selectively bind to CD44v6-expressing GC cells was demonstrated using an isogenic human GC cell line, previously established and explored by our group [ 15 , 16 , 23 ]. Overall, this study provides new insights for the development of more effective GC-targeting diagnostic and therapeutic approaches and emphasizes the modular and bioorthogonal nature of our strategy that can be broadly applied to develop novel targeted approaches.…”

Section: Introductionmentioning

confidence: 99%

Engineering Modular Half-Antibody Conjugated Nanoparticles for Targeting CD44v6-Expressing Cancer Cells

et al. 2021

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Gastric cancer (GC) remains a major cause of death worldwide mainly because of the late detection in advanced stage. Recently, we proposed CD44v6 as a relevant marker for early detection of GC, opening new avenues for GC-targeted theranostics. Here, we designed a modular nanoscale system that selectively targets CD44v6-expressing GC cells by the site-oriented conjugation of a new-engineered CD44v6 half-antibody fragment to maleimide-modified polystyrene nanoparticles (PNPs) via an efficient bioorthogonal thiol-Michael addition click chemistry. PNPs with optimal particle size (200 nm) for crossing a developed biomimetic CD44v6-associated GC stromal model were further modified with a heterobifunctional maleimide crosslinker and click conjugated to the novel CD44v6 half-antibody fragment, obtained by chemical reduction of full antibody, without affecting its bioactivity. Collectively, our results confirmed the specific targeting ability of CD44v6-PNPs to CD44v6-expressing cells (1.65-fold higher than controls), highlighting the potential of CD44v6 half-antibody conjugated nanoparticles as promising and clinically relevant tools for the early diagnosis and therapy of GC. Additionally, the rational design of our nanoscale system may be explored for the development of several other nanotechnology-based disease-targeted approaches.

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“…In oral cancer, CD44v4 is associated to chemoresistance to cisplatin via the activation of the MEK/ERK1/2 pathway whereas CD44v6 is associated to invasiveness via the inactivation of the PI3K/AKT/GSK3B pathway [ 118 ] as it regulates MMP-9 expression [ 119 ]. CD44v6 positive gastric cells also survive longer and have lower apoptosis after cisplatin treatment [ 120 ]. CD44 promotes tumor resistance to ROS- and chemotherapy-induced stress by regulating some of the transcription coactivators of the tumor suppressor Hippo signaling pathway that consists of a cascade of conserved kinases and transcription coactivators [ 121 , 122 ].…”

Section: Main Textmentioning

confidence: 99%

Proteolytic Processing of CD44 and Its Implications in Cancer

Medrano-González¹,

Rivera-Ramírez²,

Montaño³

et al. 2021

Stem Cells International

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CD44 is a transmembrane glycoprotein expressed in several healthy and tumor tissues. Modifications in its structure contribute differently to the activity of this molecule. One modification that has provoked interest is the consecutive cleavage of the CD44 extracellular ectodomain by enzymes that belong mainly to the family of metalloproteases. This process releases biologically active substrates, via alternative splice forms of CD44, that generate CD44v3 or v6 isoforms which participate in the transcriptional regulation of genes and proteins associated to signaling pathways involved in the development of cancer. These include the protooncogene tyrosine-protein kinase Src (c-Src)/signal transducer and activator of transcription 3 (STAT3), the epithelial growth factor receptor, the estrogen receptor, Wnt/βcatenin, or Hippo signaling pathways all of which are associated to cell proliferation, differentiation, or cancer progression. Whereas CD44 still remains as a very useful prognostic cell marker in different pathologies, the main topic is that the generation of CD44 intracellular fragments assists the regulation of transcriptional proteins involved in the cell cycle, cell metabolism, and most importantly, the regulation of some stem cell-associated markers.

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Expression of CD44v6-Containing Isoforms Influences Cisplatin Response in Gastric Cancer Cells

Cited by 14 publications

References 41 publications

CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

Engineering Modular Half-Antibody Conjugated Nanoparticles for Targeting CD44v6-Expressing Cancer Cells

Proteolytic Processing of CD44 and Its Implications in Cancer

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