Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer

Pályi-Krekk, Zsuzsanna; Barok, Márk; Isola, Jorma; Tammi, Markku; ̋si, János Szöllo; Nagy, Péter

doi:10.1016/j.ejca.2007.08.018

Cited by 131 publications

(107 citation statements)

References 47 publications

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“…Both stromal cells and tumor cells may provide HA to the TME, and our results demonstrate that an HA high TME contributes to limiting the access of NK cells and therapeutic antibody into the tumor. Although, while we have not observed reduced antibody binding to HA high tumor cells in vitro, receptor masking in HA high tumors in vivo may contribute to resistance to mAb therapy (34,35). Thus, enhanced tumor access of NK cells and antibody, as well as increased antibody binding to exposed target receptors, can be achieved by depletion of stromal HA with PEGPH20 treatment.…”

Section: Discussionmentioning

confidence: 95%

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Singha

Nekoroski

Zhao

et al. 2015

Molecular Cancer Therapeutics

116

101

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Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HA high ) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER2 3þ primary breast tumors and approximately 40% of EGFR þ head and neck squamous cell carcinomas are HA high , and hypothesized that HA high tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HA high tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HA high tumor cells, and greatly enhanced trastuzumab-or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HA high tumors, resulting in enhanced trastuzumab-and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HA high matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HA high tumors.

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Section: Discussionmentioning

confidence: 95%

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Singha

Nekoroski

Zhao

et al. 2015

Molecular Cancer Therapeutics

116

101

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“…[19][20][21][22][23][24][25] Moreover, the overall response rate of women diagnosed with HER2-positive metastatic breast cancer and treated with trastuzumab as a single first-line agent is only 26%; that is, > 70% of HER2-overexpressing metastatic breast carcinomas show a resistance to trastuzumab ab initio. A variety of possible mechanisms of escape from trastuzumab appear to involve many of the same biomarkers that have been implicated in the biology of CS-like cells: e.g., the overexpression of the stem cell-related marker CD44, leading to a loss or blockage of the trastuzumab-binding site at the extracellular domain of HER2; 26,27 the upregulation of stem cell markers, such as CXCR4, β1 integrin or Notch-1, [28][29][30][31][32] leading to the activation of alternative pathways circumventing HER2 signaling and the upregulation of pro-survival mediators, such as the inhibitor of apoptosis survivin. 33 Accordingly, it has been suggested that, although trastuzumab effectively targets cancer-initiating cells, a clinical resistance to trastuzumab may counter-intuitively be driven by breast CSCs.…”

Section: Epithelial-to-mesenchymal Transition (Emt) Confers Primary Rmentioning

confidence: 99%

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

et al. 2012

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“…2). Despite its paradoxical HER2 gene amplification, ER/PR-negative JIMT-1 cells have repeatedly been classified as basal-like breast cancer cells mainly due to the fact that they express both basal CK5/ CK14 and luminal CK8/CK18 cytokeratins (11,13). Highresolution genomic profiles have confirmed that JIMT-1 cells have the closest resemblance to the HER2 + breast cancer subtype but also to the stem/progenitor (basal-like) breast tumors (23).…”

Section: Jimt-1 Breast Cancer Cells: a Model For Studying Her2-overexmentioning

confidence: 80%

“…Although significant amount of pre-clinical and clinical research has been dedicated to elucidate molecular mechanisms that could explain the appearance of acquired resistance to trastuzumab (7)(8)(9)(10), there have been few studies addressing the ultimate molecular mechanisms that could explain de novo (i.e. intrinsic or primary) resistance to trastuzumab (11)(12)(13). Indeed, HER2 status yet remains as the only available biomarker for selecting breast cancer patients for trastuzumab-based therapy.…”

Section: Introductionmentioning

confidence: 99%

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

et al. 2010

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Abstract.Pioneering clinical studies in de novo refractoriness to the anti-HER2 monoclonal antibody trastuzumab have suggested that HER2 gene-amplification can take place also in a basal-like molecular background to generate basal/HER2 + tumors intrinsically resistant to trastuzumab. Here, we first investigated the unique histogenesis of the basal/HER2 + phenotype in breast carcinomas. The presence of basal CK5/CK6 cytokeratin expression in HER2 + tumors revealed a significant overlap in the histological features of HER2 + /CK5/6 + and basal-like breast carcinomas. Basal/ HER2 + tumors were typically poorly differentiated, highgrade invasive ductal carcinomas with large geographic necrosis, pushing margins of invasion, syncytial arrangement of tumor cells, ribbon-or festoon-like architecture, squamous metaplasia, stromal lymphocytic infiltrates, high mitotic index and strong p53 positivity. Secondly, we performed low-scale proteomic approaches in JIMT-1 cells, a unique model of HER2-gene amplified trastuzumab-resistant breast carcinoma with a basal-like phenotype, to develop biomarker signatures that may differentiate trastuzumab-responsive from non-responsive tumors. When applying antibody-based array technology to the extracellular milieu of trastuzumabrefractory JIMT-1 and trastuzumab-sensitive SKBR3 cell cultures, JIMT-1 cells were found to secrete higher amounts of several growth factors including amphiregulin, EGF, IGFBP-6, PDGF-AA, neurotrophins, TGFß and VEGF. Semiquantitative signaling node multi-target sandwich ELISAs revealed that JIMT-1 cells drastically overactivate RelA, the prosurvival subunit of NF-κB as compared to trastuzumabsensitive luminal/HER2 + SKBR3 cells. When simultaneously assessing the activation status of 42 receptor tyrosine kinases (RTK) using a human phospho-RTK array, JIMT-1 cells were found to constitutively display hyperactivation of the insulin-like growth factor-I receptor (IGF-1R). High-content immunofluorescence imaging revealed that activated IGF-1R mainly localized at focal adhesion-like structures in JIMT-1 cells. In vitro wound healing assays suggested that this functional reorganization of the JIMT-1 cytoskeletal reorganization may account for an exacerbated trastuzumab-refractory 'migratogenic' phenotype. Forthcoming studies should validate the notion that identification of basal-like immunophenotypes and/or basal-like molecular signatures within HER2 + breast carcinomas may provide rapid means to define subgroups of breast cancer patients likely to display resistance to trastuzumab ab initio.

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Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer

Abstract: Although trastuzumab, a recombinant humanized anti-ErbB2 antibody, is widely used in the treatment of breast cancer, neither its mechanism of action, nor the factors leading to resistance are fully understood. We have previously shown that antibody-dependent cellular

Cited by 131 publications

References 47 publications

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

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