Liver cancer is the fourth leading cause of cancer-related death globally, with hepatocellular carcinoma (HCC) being the most commonly occurring primary cancer, making up around 75-85% of cases.
HCC can be categorized into a number of histological subtypes, demonstrating the disease’s heterogeneity. This heterogeneity, including the plasticity of the cancer cells, is considered to be partially influenced by the microenvironment.
The primary cytokine signaling pathway for the progression and growth of HCC cells is the TGF-β signaling pathway, which joins the tumor cells and microenvironment.
This pathway is named for a polypeptide associated with the transforming growth factor beta superfamily of cytokines.
TGF-β has the capacity to inhibit hepatocyte proliferation and suppress progenitor properties of hepatocyte-initiating cells and is involved in several functions, including cellular differentiation, migration and proliferation.
This is accomplished by inhibiting the TGF-β type II receptor (TGFBR2) and stimulating TGF-β type I receptor (TGFBR1)-downstream Smad2/3 transcription factors.
This disease is extremely complex, which is highlighted by studies that have shown how tumor progression is accelerated by TGF-β1 signaling stimulating angiogenesis and encouraging metastasis.
High TGF-β1 expression combined with low TGFBR2 expression is predictive of poor outcomes in HCC.
Additionally, the expression of TGFBR2 appears to be critical in phenotypic shifting from TGF-β1-dependent proliferation inhibition to progression of the disease.
The complexity of the TGF-β signaling pathway in HCC development and progression is revealed by the conditional functions of TGF-β1 signaling the necessity for sophisticated therapeutics.
Part of the TGF-β superfamily, BMP proteins can bind BMPR2 and BMPR1 on the surface of the cell and phosphorylating Smad1/5/8 downstream.
The crosstalk between the BMP and TGF-β pathways has attracted much attention and been a significant focus in the field of renal disease and bone formation, with the development of these diseases connected to the balance between TFG-β and BMP signaling.
Predicated on this information, a team of Chinese researchers led by Junya Ning suggested that the imbalance between the TGF-β and BMP pathways could be related to the progression of HCC.
Presently, treatments for HCC do not effectively prevent the recurrence of tumors and metastasis, thereby threatening long-term survival.
Therefore, when combatting the disease, there is the need to formulate novel strategies in order to do so.
Ning et al. set out to study the interactive network between BMP and TGF-β pathways in HCCs.
They utilized the gene-expression profiles of 359 HCC samples provided by The Cancer Genome Atlas, in conjunction with 197 primary HCC tissues supplied by Tianjin Medical University Cancer Institute & Hospital.
The aim was to identify the key factors organizing the interaction between the TGF-β and BMP pathways and determine the imbalance of TGF-β1/BMP-7 pathways in HCCs.
By studying RNA sequencing data extracted from HCC samples, they discovered that the imbalance between TGF-β1/BMP-7 pathways was discernable at the mRNA level and affiliated with poor clinical outcomes and aggressive pathological features.
The significance of this imbalance was then investigated at the protein level by evaluating and contrasting two cohorts.
Cohort I included 64 patients who had each supplied samples of primary HCC tissues, which were then subjected to immunohistochemistry staining to identify key proteins along the TGF-β1 pathway and BMP-7 pathway.
Generally, survival was in accordance with a comparison of the expression of various proteins.
It was seen that patients with specific protein profiles — low TGFBR2, high TGF-β1, high ACVR1 and high BMP-7 expression — had limited survival rates compared to those in the different expression groups.
They also discovered that a serious negative correlation of TGFBR2 expression was related to ACVR1 expression, and samples expressing low TGFBR2 and high ACVR1 demonstrated worse clinical outcomes than the other patients.
Cohort II was made up of 133 primary HCC tissue samples, which were used to identify expression patterns of TGFBR2 and ACVR2 in situ utilizing immunofluorescence (IF) staining in combination with multispectral imaging.
This methodology included the imaging using the TissueFAXS SPECTRA by TissueGnostics after carrying out the washing and blocking of slides with antibodies.
The TissueFAXS SPECTRA is a multispectral tissue cytometer predicated on a liquid crystal tunable filter (LCTF) and spectral unmixing engine of StrataQuest analysis software which facilitates the acquisition of an increased number of fluorescence channels for high content phenotyping in tissue sections.
Enabling the separation of multiple colors, the TissueFAXS SPECTRA permitted imaging of the liver slides, which revealed the DAPI staining, hepatocyte paraffin antigen 1, TGFBR2 and ACVR1.
The autofluorescence was expelled from the process of spectral unmixing; the spectral signature of non-specific staining in the tissue (typical in liver tissue) was identified and extracted utilizing the spectral unmixing engine and the multispectral data acquired by the LCTF in the form of a LAMBDA stack.
Corresponding to previous findings, TGF-β1/BMP-7 pathway imbalance was corroborated at the protein level and associated with aggressive pathological features and dire clinical outcomes.
Conducting additional experimentation, Ning et al. revealed that the imbalance of TGF-β1/BMP-7 pathways significantly amplified HCC cell invasion — via the upregulation of the genes affiliated with epithelial-mesenchymal transition (EMT) and stemness — through encouraging the production of inhibitor of differentiation 1 (ID1).
This imbalance was seen to be regulated by a microRNA (miR)-17-92 cluster, which stimulates the imbalance of TGF-β1/BMP-7 pathways by impeding with TGFBR2 mRNA expression and improving ACVR1 protein expression via Smurf1 (a gene encoding enzyme that behaves as a negative regulator of the BMP signaling pathway) silencing.
It was then established that M2-polarized tumor-associated macrophages (M2-TAMs) influence the instability of TGF-β1/BMP-7 pathways in HCCs. By releasing extracellular vesicles containing the miR-17-92 cluster, M2-TAMs intensify the level of clusters within HCC cells, thereby aggravating the instability of the TGF-β1/BMP-7 pathway.
Finally, using mice xenografts, reversal of the pathway imbalance was seen to in effect attenuate M2-TAM-abundant HCC growth and metastasis in vivo.
Altogether, this led Ning et al. to suggest that disparity between the TGF-β1/BMP-7 pathways is a viable prognostic biomarker for HCC, and restoration of this balance might function as a possible strategy to combat HCCs.
This study has considerable implications in understanding HCC growth and progression and can usher in unique and sophisticated therapeutics for the treatment of the disease.
However, due to the acute heterogeneity discovered within the tumor and microenvironment, as well as the intricate etiologic diversity of HCCs, Ning et al. call attention to the fact that patient-derived xenograft HCC models are necessary to legitimize the therapeutic efficacy of the TGF-β1/BMP-7 pathway imbalance.
- Ning, J., et al. (2021). Imbalance of TGF-β1/BMP-7 Pathways Induced by M2-polarized Macrophages Promotes Hepatocellular Carcinoma Aggressiveness. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2021.02.016.
- Shi, C., et al. (2014). Incorporating spatial information in spectral unmixing: A review. Remote Sensing of Environment. https://doi.org/10.1016/j.rse.2014.03.034.
TissueGnostics (TG) is an Austrian company focusing on integrated solutions for high content and/or high throughput scanning and analysis of biomedical, veterinary, natural sciences, and technical microscopy samples.
TG has been founded by scientists from the Vienna University Hospital (AKH) in 2003. It is now a globally active company with subsidiaries in the EU, the USA, and China, and customers in 30 countries.
TG scanning systems are currently based on versatile automated microscopy systems with or without image analysis capabilities. We strive to provide cutting-edge technology solutions, such as multispectral imaging and context-based image analysis as well as established features like Z-Stacking and Extended Focus. This is combined with a strong emphasis on automation, ease of use of all solutions, and the production of publication-ready data.
The TG systems offer integrated workflows, i.e. scan and analysis, for digital slides or images of tissue sections, Tissue Microarrays (TMA), cell culture monolayers, smears, and other samples on slides and oversized slides, in Microtiter plates, Petri dishes and specialized sample containers. TG also provides dedicated workflows for FISH, CISH, and other dot structures.
TG analysis software apart from being integrated into full systems is fully standalone capable and supports a wide variety of scanner image formats as well as digital images taken with any microscope.
TG also provides routine hematology scanning and analysis systems for peripheral blood, bone marrow, and body fluids.
TG continuously cooperates with research groups and other companies in the industry to provide novel tools and applications to its customers.
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