Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

Santos-Ferreira

et al. 2021

Cancers

Biglycan (BGN gene), an extracellular proteoglycan, has been described to be associated with cancer aggressiveness. The purpose of this study was to clarify the clinical value of biglycan as a biomarker in multiple independent GC cohorts and determine the in vitro and in vivo role of biglycan in GC malignant features. We found that BGN is commonly over-expressed in all analyzed cohorts, being associated with disease relapse and poor prognosis in patients with advanced stages of disease. In vitro and in vivo experiments demonstrated that biglycan knock-out GC cells display major phenotypic changes with a lower cell survival, migration, and angiogenic potential when compared with biglycan expressing cells. Biglycan KO GC cells present increased levels of PARP1 and caspase-3 cleavage and a decreased expression of mesenchymal markers. Importantly, biglycan deficient GC cells that were supplemented with exogenous biglycan were able to restore biological features, such as survival, clonogenic and migratory capacities. Our in vitro and in vivo findings were validated in human GC samples, where BGN expression was associated with several oncogenic gene signatures that were associated with apoptosis, cell migration, invasion, and angiogenesis. This study provided new insights on biglycan role in GC that should be taken in consideration as a key cellular regulator with major impact in tumor progression and patients’ clinical outcome.

Section: Discussionmentioning

confidence: 99%

The Extracellular Small Leucine-Rich Proteoglycan Biglycan Is a Key Player in Gastric Cancer Aggressiveness

Santos-Ferreira

et al. 2021

Cancers

“…Indeed, genomic and transcriptomic analysis have demonstrated that the activated gene sets in response to TGF-β signaling are involved in regulating various pathophysiological processes including EMT, wound healing, angiogenesis, and dissemination ( Hugo et al, 2016 ). On the other hand, TGF-β can regulate immune response by orchestrating the crosstalk of multiple cell types in the TME, including CAFs, lymphocytes, and endothelial cells ( Korneev et al, 2017 ; Chakravarthy et al, 2018 ; Kesh et al, 2020 ). TGF-β can inhibit the proliferation and differentiation of anti-tumor T cells by increasing the expression of CD25 and Foxp3 ( Löffek, 2018 ).…”

Section: Tme-driven Adaptive Mechanisms Of Therapy Resistancementioning

confidence: 99%

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Gao

et al. 2021

Front. Cell Dev. Biol.

107

Cancer is a disease which frequently has a poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments frequently impedes the clinical outcomes. Besides the active resistance driven by genetic and epigenetic alterations in tumor cells, the tumor microenvironment (TME) has also been reported to be a crucial regulator in tumorigenesis, progression, and resistance. Here, we propose that the adaptive mechanisms of tumor resistance are closely connected with the TME rather than depending on non-cell-autonomous changes in response to clinical treatment. Although the comprehensive understanding of adaptive mechanisms driven by the TME need further investigation to fully elucidate the mechanisms of tumor therapeutic resistance, many clinical treatments targeting the TME have been successful. In this review, we report on recent advances concerning the molecular events and important factors involved in the TME, particularly focusing on the contributions of the TME to adaptive resistance, and provide insights into potential therapeutic methods or translational medicine targeting the TME to overcome resistance to therapy in clinical treatment.

“…The ECM in breast tumors is integral to the invasion and metastasis of BC. In recent years, increasing evidence has indicated that the ECM may also play an important role in mediating resistance to existing treatments (77)(78)(79). It provides an adhesion matrix and specific matrix components that promote survival mechanisms to support and induce stem cell pathways and enhance cell metastasis and invasion (80).…”

Section: Treatment Resistance Induced By Ecmmentioning

confidence: 99%

Extracellular Matrix: Emerging Roles and Potential Therapeutic Targets for Breast Cancer

Zhao

Zheng

et al. 2021

Front. Oncol.

Increasing evidence shows that the extracellular matrix (ECM) is an important regulator of breast cancer (BC). The ECM comprises of highly variable and dynamic components. Compared with normal breast tissue under homeostasis, the ECM undergoes many changes in composition and organization during BC progression. Induced ECM proteins, including fibrinogen, fibronectin, hyaluronic acid, and matricellular proteins, have been identified as important components of BC metastatic cells in recent years. These proteins play major roles in BC progression, invasion, and metastasis. Importantly, several specific ECM molecules, receptors, and remodeling enzymes are involved in promoting resistance to therapeutic intervention. Additional analysis of these ECM proteins and their downstream signaling pathways may reveal promising therapeutic targets against BC. These potential drug targets may be combined with new nanoparticle technologies. This review summarizes recent advances in functional nanoparticles that target the ECM to treat BC. Accurate nanomaterials may offer a new approach to BC treatment.