Targeting the hepatocyte growth factor/Met pathway in cancer

Silva, Dinuka M. De; Roy, Arpita Singha; Kato, Takashi; Cecchi, Fabiola; Lee, Young Ho; Matsumoto, Kunio; Bottaro, Donald P.

doi:10.1042/bst20160132

Cited by 50 publications

(42 citation statements)

References 109 publications

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“…Most importantly, the molecular differences create opportunities for various treatment modalities toward a more individualized therapy approach. For example, MET pathway-targeted anticancer therapies may be more effective in PDACs of the immune-escape subtype, to additionally target EMT-like tumor budding, as mutations in the receptor tyrosine kinases MET and ERBB4 were more frequent in the immuneescape cases (38,39). In a recent study, dual MET and ERBB inhibition was shown to overcome intratumor plasticity in osimertinib-resistant advanced non-small cell lung cancer (40).…”

Section: Discussionmentioning

confidence: 99%

Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance

Wartenberg

Cibin

Zlobec

et al. 2018

Clinical Cancer Research

144

167

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Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings. A well-characterized PDAC cohort ( = 110) underwent next-generation sequencing with a hot spot cancer panel while next-generation tissue microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM), and DNA mismatch repair proteins. Previous data on FOXP3 were integrated. Immune cell counts and protein expression were correlated with tumor-derived driver mutations, clinicopathologic features (TNM 8th edition, 2017), survival, and epithelial-mesenchymal transition (EMT)-like tumor budding. Three PDAC subtypes were identified: the "immune escape" (54%), poor in T and B cells and enriched in FOXP3 regulatory T cells (Treg), with high-grade budding, frequent ,, and mutations, and poor outcome; the "immune rich" (35%), rich in T and B cells and poorer in FOXP3 Tregs, with infrequent budding, lower and mutation rate, and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes ( and ), and the best outcome; and the "immune exhausted" (11%), with immunogenic microenvironment and two subpopulations-one with PD-L1 expression and a high mutation rate and a microsatellite-unstable subpopulation with a high prevalence of mutations. The combination of low budding, low stromal FOXP3 counts, presence of TLTs, and absence of mutations confers significant survival advantage in patients with PDAC. Immune host responses correlate with tumor characteristics, leading to morphologically recognizable PDAC subtypes with prognostic/predictive significance. .

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Section: Discussionmentioning

confidence: 99%

Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance

Wartenberg

Cibin

Zlobec

et al. 2018

Clinical Cancer Research

144

167

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“…Limiting neutrophil recruitment by blocking cMET promotes the efficacy of adoptive T cell transfer and checkpoint therapy in murine melanoma ( 196 ). Antagonists of the HGF/cMET pathway have been developed and are being tested in multiple types of human cancer ( 197 ).…”

Section: Targeting Neutrophil Activity In Cancer Therapymentioning

confidence: 99%

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

et al. 2020

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Over the last decades, cancer immunotherapies such as checkpoint blockade and adoptive T cell transfer have been a game changer in many aspects and have improved the treatment for various malignancies considerably. Despite the clinical success of harnessing the adaptive immunity to combat the tumor, the benefits of immunotherapy are still limited to a subset of patients and cancer types. In recent years, neutrophils, the most abundant circulating leukocytes, have emerged as promising targets for anti-cancer therapies. Traditionally regarded as the first line of defense against infections, neutrophils are increasingly recognized as critical players during cancer progression. Evidence shows the functional plasticity of neutrophils in the tumor microenvironment, allowing neutrophils to exert either pro-tumor or anti-tumor effects. This review describes the tumor-promoting roles of neutrophils, focusing on their myeloid-derived suppressor cell activity, as well as their role in tumor elimination, exerted mainly via antibody-dependent cellular cytotoxicity. We will discuss potential approaches to therapeutically target neutrophils in cancer. These include strategies in humans to either silence the pro-tumor activity of neutrophils, or to activate or enhance their anti-tumor functions. Redirecting neutrophils seems a promising approach to harness innate immunity to improve treatment for cancer patients.

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“…Concerning HGF/c-MET specific drugs, two major classes are described: the small molecules tyrosine kinase inhibitors (TKIs), whose mechanism of action is mainly intracellular and the human monoclonal antibodies that recognize extracellular components. A comprehensive review of these drugs was performed by De Silva et al (2017) [ 127 ]. Monoclonal antibodies targeting HGF/c-MET pathways have been evaluated in clinical trials and are able to recognize the HGF or the c-MET extracellular domains, ultimately disturbing HGF/c-MET interaction and signaling.…”

Section: Strategies To Target Hgf/cmet–ecm Interactionsmentioning

confidence: 99%

Extracellular Matrix Influencing HGF/c-MET Signaling Pathway: Impact on Cancer Progression

Noriega-Guerra

Freitas

2018

IJMS

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The extracellular matrix (ECM) is a crucial component of the tumor microenvironment involved in numerous cellular processes that contribute to cancer progression. It is acknowledged that tumor–stromal cell communication is driven by a complex and dynamic network of cytokines, growth factors and proteases. Thus, the ECM works as a reservoir for bioactive molecules that modulate tumor cell behavior. The hepatocyte growth factor (HGF) produced by tumor and stromal cells acts as a multifunctional cytokine and activates the c-MET receptor, which is expressed in different tumor cell types. The HGF/c-MET signaling pathway is associated with several cellular processes, such as proliferation, survival, motility, angiogenesis, invasion and metastasis. Moreover, c-MET activation can be promoted by several ECM components, including proteoglycans and glycoproteins that act as bridging molecules and/or signal co-receptors. In contrast, c-MET activation can be inhibited by proteoglycans, matricellular proteins and/or proteases that bind and sequester HGF away from the cell surface. Therefore, understanding the effects of ECM components on HGF and c-MET may provide opportunities for novel therapeutic strategies. Here, we give a short overview of how certain ECM components regulate the distribution and activation of HGF and c-MET.

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Targeting the hepatocyte growth factor/Met pathway in cancer

Cited by 50 publications

References 109 publications

Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance

Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

Extracellular Matrix Influencing HGF/c-MET Signaling Pathway: Impact on Cancer Progression

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