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(a) Sections showing low-grade tumor budding in colorectal carcinoma (H and E x20×). (b) Sections showing high-grade tumor budding in colorectal carcinoma (H and E x40×). (c) Immunohistochemical study showing pancytokeratin positivity in malignant cells in CRC (PanCK x20×)
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Background:
Tumor budding (TB) is a promising prognostic factor in colorectal cancer (CRC) that is independent of tumor-node-metastasis (TNM) staging. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is a stem cell marker and a member of the canonical Wnt-signaling cascade. It is involved in colorectal carcinogenesis. However, it...
Contexts in source publication
Context 1
... grades by H and E staining and CK-IHC TB was first evaluated in H and E stained sections [ Figure 1a and b] followed by CK-IHC [ Figure 1c]. Among 92 CRC cases, H and E stained sections revealed low-and high-grade budding in 55 and 37 tumors, respectively, whereas CK-IHC showed low-and high-grade budding in 31 and 61 tumors, respectively. ...
Context 2
... grades by H and E staining and CK-IHC TB was first evaluated in H and E stained sections [ Figure 1a and b] followed by CK-IHC [ Figure 1c]. Among 92 CRC cases, H and E stained sections revealed low-and high-grade budding in 55 and 37 tumors, respectively, whereas CK-IHC showed low-and high-grade budding in 31 and 61 tumors, respectively. ...
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Background:
This study aimed to explore the potentially predictive role and dynamic changes of immune checkpoints on T cell subsets in patients with breast cancer receiving neoadjuvant chemotherapies.
Methods:
Fluorescent multiplex immunohistochemistry (mIHC) was used to stain CD4, CD8, PD1, TIM3, and cytokeratins simultaneously in paired breast...
Citations
... Indeed, there are several biological features supporting the MACC1-LGR5 link, i.e., the involvement of MACC1 and of LGR5 in clathrin-mediated endocytosis [37,38], their localization at the tumor invasion front [39,40], their role in core clock regulation [41,42] and their impact on craniofacial development [43,44]. Further, the regulation of both genes shares defined signaling pathways, such as the Wnt signaling pathway [45,46]. ...
Simple Summary
We discovered a novel association of cancer and stemness. In particular, we demonstrate an MACC1—LGR5 link by transcriptional regulation of the crucial stemness gene LGR5 by MACC1, the inducer of tumor initiation, progression and metastasis. We show this regulation by using 2D and 3D cell culture models, in CRC-derived PDX mouse models and in human CRC patient samples. This study indicates that the metastasis inducer MACC1 acts not only as a cancer stem cell-associated marker, but also as a regulator of LGR5 expression and LGR5-mediated stem cell properties. Thus, interventional approaches targeting MACC1 would potentially improve further targeted therapies for CRC patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation.
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcomes. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our MACC1 transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and the CSC-associated invasive phenotype based on patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs) and human CRC cell lines. We showed that CD44-enriched CSCs from PDO models express significantly higher levels of MACC1 and LGR5 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PDO and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with the CSC markers CD44, NANOG and LGR5 in PDO models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter, uncovering the long-known CSC marker LGR5 as a novel essential signaling mediator employed by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by a significant positive correlation of MACC1 with LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis inducer MACC1 acts as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation.
... These findings support the view that cell proliferation and migration are mutually exclusive processes and that the transition from cell proliferation to invasion may be triggered by hypoxia. Moreover, the fact that budding tumor cells frequently overexpress stem cell markers, such as LGR5, ALDH1, and CD44, suggests the self-renewal capacity of these cells, including those at metastatic sites [26,[59][60][61][62]. ...
Hepatocellular (HCC) and intrahepatic cholangiocarcinoma (ICC), the most common primary tumors of the liver, are among the most important causes of cancer deaths worldwide. Because patients with primary liver tumors are frequently diagnosed at an advanced stage and have high mortality, many efforts have been made to identify new markers to determine their behavior and treatment, similar to those in other solid organ tumors. Recently, morphological assessment of tumor budding (TB) has been revealed as a promising prognostic finding to predict tumor behavior and survival across several different tumor types. Currently, the TB score in colorectal cancer has been revealed as an important parameter in pathology report protocols to determine the course of the disease. Regarding the liver, despite enormous data showing that many mechanisms involved in TB are associated with tumor behavior in both HCC and ICC, studies focusing on the role of TB in predicting the behavior and prognosis of these tumors have started to be investigated very recently. The purpose of this review is to present data about TB in primary tumors of the liver, pointing out the potential role of this parameter in determining the course of the disease, and emphasize the need to increase the number of further studies focusing on the evaluation of this parameter with an overview of the mechanisms involved in TB.
... Furthermore, LGR5 overexpression was observed in 48.60% of individuals with the TNBC subtype (Fig. 3B). Two studies noticed that LGR5 overexpressed in 39 There was one study in which the immunohistochemical staining results of LGR5 in breast cancer tissue were compared with normal tissue samples and the result showed that the rate of LGR5 in breast cancer was 16.36 times more than the normal sample as the control group (Odds Ratio: 16.36 CI95%:9.85-27.17 ) [27]. Fig. (1). ...
... Several studies showed an aberrant expression of intracellular Wnt pathway in tumors, involved in various cellular processes: proliferation, differentiation, and migration [37]. Reports suggested that LGR5 knockdown can potentially suppress tumor growth [38,39]. However, Walker et al. [40] highlighted that breaking down LGR5 promotes the function of EMT genes and the aggressiveness of colorectal cancer. ...
Background and objective:
Breast cancer is the world's most common malignancy. Despite significant advances in the diagnosis and treatment of the disease, the associated mortality rate is still high. Tumor initiating cells known as cancer stem cells with unique abilities are suspected responsible for therapy failure and poor prognosis. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker which promotes aggressive features in breast cancer cells. So, the aim of this study was to perform a systematic review and meta-analysis to evaluate LGR5 as a therapeutic target for breast cancer.
Methods:
This systematic review and meta-analysis were performed using databases of Web of Science, Scopus, and PubMed. We searched these databases with LGR5 and Breast Cancer and related keywords based on mesh database until Oct12, 2021. All studies that reported the rate of LGR5 high expression with Immunohistochemistry in breast cancer patients were included in this review. We used the STATA and random effect model for data analysis.
Results:
Finally, 7 studies including 2632 breast cancer samples were studied. The pooled prevalence of LGR5 high expression in breast cancer was 36 % (CI95%: 26-47.5%, I2= 95.5) and in triple negative was 48.6% (CI95%: 38.4-58.7%, I2= 0.0).
Conclusion:
Our findings show that the rate of LGR5 high expression in breast cancer in general and especially in triple negative was considerable and it seems that this is a potential therapeutic target for breast cancer.
... Moreover, nuclear β-catenin signaling plays an important role in the induction of epithelialmesenchymal transition (EMT)/cancer stem cell (CSC) properties through increased Slug and decreased Ecadherin expression in endometrial and colon carcinoma cells [34,35]. Leucine-rich repeat-containing G-proteincoupled receptor 5 (Lgr5), a target of Wnt pathway signaling and canonical marker of colorectal CSC, also contributes to the formation of budding features in CRC [36]. In our current study, stromal PD-L1+ immune cell infiltration was significantly associated with nuclear β-catenin+ tumor budding and tumor lymph/vascular invasion in CRC without NCRT. ...
Programmed cell death‐1 (PD‐1) and its ligand (PD‐L1) are significant mediators of immune suppression in the tumor microenvironment. We focused on the immunological impact of PD‐1/PD‐L1 signaling during tumor progression in colorectal carcinoma (CRC) and its association with resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal carcinoma (LAd‐RC). Histopathological and immunohistochemical analyses of 100 CRC cases (including 34 RC) without NCRT and 109 NCRT‐treated LAd‐RC cases were performed. Membranous tumoral PD‐L1 expression was identified in 9 of 100 (9%) CRC cases, including 1 of 34 (2.9%) RC cases, but PD‐L1 immunopositivity was not associated with any clinicopathological factors, with the exception of deficient mismatch repair (dMMR) status. In contrast, stromal PD‐L1+ immune cells, which frequently exhibited coexpression of PD‐1 and CD8 markers, were significantly correlated with tumor vessel invasion, nuclear β‐catenin+ tumor budding cancer stem cell (CSC)‐like features, and unfavorable prognosis. In the LAd‐RC cases, stromal CD8+ (but not PD‐L1+) immune cell infiltration in pretreatment‐biopsied samples was significantly and positively associated with therapeutic efficacy. After NCRT, tumoral PD‐L1 expression was observed in only 2 of 83 (2.4%) tumors, independent of dMMR status, whereas high stromal PD‐L1+ and tumoral nuclear β‐catenin positivity were significantly linked to a poor response to NCRT and high tumor budding features. In addition, high stromal PD‐L1 immunoreactivity was significantly associated with poorer overall survival. In conclusion, a combination of stromal PD‐L1+ immune cells and nuclear β‐catenin+ tumor budding may contribute to tumor progression in CRC and resistance to NCRT in LAd‐RC, through formation of niche‐like lesions that exhibit immune resistance and CSC properties.
... It has been reported to be up-regulated in various types of tumours including CRC. Expression of LGR5 has been reported in the invasive area of the tumour (n=99) [40]. The results showed a significant association between LGR5 and TB as well as TNM stages and other adverse clinical features such as tumour invasion and lymph node metastasis in CRC [40]. ...
... Expression of LGR5 has been reported in the invasive area of the tumour (n=99) [40]. The results showed a significant association between LGR5 and TB as well as TNM stages and other adverse clinical features such as tumour invasion and lymph node metastasis in CRC [40]. ...
Colorectal cancer (CRC) is the third most common cancer worldwide. Poor survival of CRC associated with the development of tumour metastasis led to the investigation of the potential biomarkers to predict outcomes in CRC patients. Tumour budding (TB) is a well-known independent prognostic marker for poor survival and disease metastasis. Therefore, it has been suggested that TB status is included in routine clinicopathological factors for risk assessment in CRC. In contrast with a vast majority of studies regarding the prognostic power of TB, there is no clear evidence pertaining to the underlying molecular mechanism driving this phenotype, or an understanding of TB relationship with the tumour microenvironment (TME). The aim of the present study is to present a comprehensive review of TB and tumour cell signalling pathways together with the cross-talk of immune cells that could drive TB formation in CRC.
... In an immunostaining study of the colorectum, vascular invasion was frequently identified with low LGR5 expression [27], which is consistent with our study. Although the above trends differ from some previous papers [28] [29], there are some molecular biological reports that reinforce our view. Low LGR5 expression may promote EMT, resulting in invasion and metastasis. ...
Background
Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a strong cancer stem cell marker in colorectal cancer; however, there are many unclear aspects of LGR5 expression in pancreatic cancer. It has been reported that the interaction between tumor cells and stroma at the fat infiltration site has a significant effect on pancreatic cancer prognosis. Therefore, we report a clinicopathological study of LGR5 expression at the fat invasion front in pancreatic cancer.
Methods
LGR5 expression was analyzed in 40 pancreatic ductal adenocarcinoma cases with RNAscope, which is a newly developed high-sensitivity in situ hybridization method. Epithelial-mesenchymal transition (EMT) was analyzed by the expression of E-cadherin and vimentin via immunohistochemistry.
Results
LGR5 -positive dots were identified in all cases, especially with glandular formation. In the fat invasion front, a high histological grade showed significantly reduced LGR5 expression compared with a low histological grade ( p =0.0126). LGR5 expression was significantly higher in the non-EMT phenotype group than in EMT phenotype group ( p =0.0003). Additionally, LGR5 expression was significantly lower in cases with high vascular invasion than in those with low vascular invasion ( p =0.0244).
Conclusions
These findings suggest that decreased LGR5 expression in the fat invasion front is associated with more aggressive biological behavior in pancreatic ductal adenocarcinoma, with higher tumor grade, EMT phenotype, and higher vascular invasion.
... The association between intense budding and adverse survival has been confirmed by other studies targeting the complex interactions between budding and inflammation/cancer microenvironment in CRC [86]. Stem cell markers, e.g., LGR5, have been shown to be present in the tumour buds [87]. ...
In global cancer statistics, colorectal carcinoma (CRC) ranks third by incidence and second by mortality, causing 10.0% of new cancer cases and 9.4% of oncological deaths worldwide. Despite the development of screening programs and preventive measures, there are still high numbers of advanced cases. Multiple problems compromise the treatment of metastatic colorectal cancer, one of these being cancer stem cells—a minor fraction of pluripotent, self-renewing malignant cells capable of maintaining steady, low proliferation and exhibiting an intriguing arsenal of treatment resistance mechanisms. Currently, there is an increasing body of evidence for intricate associations between inflammation, epithelial–mesenchymal transition and cancer stem cells. In this review, we focus on inflammation and its role in CRC stemness development through epithelial–mesenchymal transition.
... Colorectal cancer is one of the third most prevalent cancers and the fourth cause of cancer-related mortality worldwide with 700,000 deaths annually (1)(2)(3)(4). In terms of gender, CRC is considered as the second most common cancer in females and the third in males (5). ...
Background & objective:
Colorectal cancer (CRC) is the third most common cancer worldwide with a high mortality rate. The main causes of death in patients are recurrence and metastasis which are mainly attributed to the small subpopulation of cells within tumors called cancer stem cells (CSCs). This study aimed to evaluate the correlation between the expression of ALDH1 and CD133 as CSC associated markers and clinicopathological characteristics in CRC.
Methods:
In this cross-sectional study, a total of 483 CRC tumor samples were immunohistochemically stained for detection of CD133 and ALDH1 markers. Correlations of marker expression with clinicopathological factors were also evaluated.
Results:
There was a significant correlation between the luminal intensity of CD133 and neural invasion (P=0.05) and between the cytoplasmic intensity of CD133 and metastasis (P=0.05). In terms of H-score, a positive significant relation was observed between cytoplasmic expression of CD133 and lymph node (P=0.02), neural (P=0.04) and vascular invasion (P=0.02). The ALDH1 cytoplasmic expression showed a significant correlation with tumor size (P=0.001).
Conclusion:
Our findings showed that increased expression of CD133 and ALDH1 is associated with tumor progression and worse outcomes in CRC patients. These markers can be good candidates for localized targeting of CSCs using antibodies. Future researches need to be improved approaches for early detection of CRC, and treatment monitoring for CRC and other cancers.
Objective:
To evaluate the association of tumor budding (TB) with prognostic histomorphological parameters in oral squamous cell carcinoma (OSCC) and to investigate the correlation of TB intensity with epithelial to mesenchymal transition (EMT).
Material and method:
A total of 200 cases diagnosed as OSCC were selected and their TB status was reviewed using Hematoxylin and eosin (H and E) and Immunohistochemistry (IHC). Correlation with histomorphological prognostic parameters was done. Also, IHC for Vimentin and E-cadherin was performed to look for EMT.
Results:
On H and E examination, TB was observed in 154/200 (77%). About 88/154 (57.14%) cases showed a high TB (>5 TB/10 hpf) which increased to 100/154 (64.9%) cases on IHC staining. The intensity of TB was significantly associated with tumor grade and depth of invasion. It was also significantly associated with reduced expression for E-Cadherin and upregulation of Vimentin establishing a pathogenetic correlation between the TB and EMT.
Conclusion:
Therefore, our results suggest that TB is associated with poor prognosis and histologically represents EMT in OSCC which further adds to the aggressiveness of the tumor.
Tumour budding (TB) consists of a small group of cells (upto 5) which have detached from the tumour bulk. TB has been studied in many malignancies including head and neck, colorectum, oesophagus, etc. However there are very few studies to determine its role in Breast cancer. This study was designed to study the role of tumour budding as a prognostic factor in Breast cancer.
To study the grade of TB in Invasive Breast Carcinoma and correlate it with known clinicopathological parameters to determine its usefulness as a prognostic factor.
In this retrospective observational study, 40 cases of modified radical mastectomy from July 2019 to December 2020 were evaluated for the tumour budding. Ethical clearance was not required as it was a secondary data collection study which did not relate to patient’s privacy, clinical examination or treatment. Significance and correlation was studied between the grade of TB and known clinicopathological parameters using Chi-square test.
Out of the 40 cases evaluated, 20 cases (50%) were of High grade TB (>/=10/10HPF), while 20 cases (50%) were of Low grade TB (<10/10HPF). Majority patients were of age group 40-60 years (60%), with primary carcinoma (52.5%) and invasive ductal type (72.5%). Higher TB was observed with Lymphnode positive cases (p=0.002), in higher TNM stage (p=0.006) and with lymphovascular invasion (p=0.000).
As higher grade tumour budding was associated with positive lymphnode status, higher tumour stage and presence of lymphovascular invasion, it can be considered as an indicator of poor prognosis in cases of breast carcinoma especially in resource poor institutes which are not equipped with sophisticated IHC and Molecular markers.
