Tumor Budding in Colorectal Carcinoma

Graham, Rondell P.; Vierkant, Robert A.; Tillmans, Lori S.; Wang, Alice H.; Laird, Peter W.; Weisenberger, Daniel J.; Lynch, Charles F.; French, Amy J.; Slager, Susan L.; Raissian, Yassaman; García, Joaquín J.; Kerr, Sarah E.; Lee, Hee Eun; Thibodeau, Stephen N.; Cerhan, James R.; Limburg, Paul J.; Smyrk, Thomas C.

doi:10.1097/pas.0000000000000504

Cited by 103 publications

(49 citation statements)

References 36 publications

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“…In our study, miRNA-148a expression was lower in cancers with tumor budding (median values accordingly 0.314 and 0.753, p = 0.011), which has been found by other studies to be associated with a more invasive phenotype and distant metastases [ 40 ] and determined as prognostic factor independent from CRC stage [ 3 , 4 ].…”

Section: Discussionsupporting

confidence: 80%

“…Only a few tumor markers (RAS and BRAF mutation, mismatch repair status) have been implemented into clinical practice [ 2 , 3 ]. Recent evidence suggests, that tumor budding, described as the presence of individual cells and small clusters of tumor cells at the invasive front of the carcinoma, could serve as an additional prognostic factor in stage II CRC [ 4 , 5 ], but there is little information regarding its significance in the advanced disease. The down-regulation of epithelial and the up-regulation of mesenchymal markers suggests that tumor budding is a morphological expression of epithelial mesenchymal transition (EMT), which is associated with tumor invasiveness, formation of metastases and resistance to chemotherapy [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding

et al. 2017

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BackgroundMiRNAs are often deregulated in colorectal cancer and might function as tumor suppressors or as oncogenes. They participate in controlling key signaling pathways involved in proliferation, invasion and apoptosis and may serve as prognostic and predictive markers. In this study we aimed to evaluate the role of miRNA-148a and miRNA-625-3p in metastatic colorectal cancer.MethodsFifty-four patients with a first-time diagnosed CRC receiving FOLFOX ± Bevacizumab were involved in the study. Tumor samples underwent routine pathology examination including evaluation for tumor budding and KRAS. MiRNA-148a and miRNA-625-3p expression analysis was done by RT-PCR. Associations between expression of both miRNAs and clinico-pathological factors, treatment outcomes and survival were analyzed.ResultsBoth miRNA-148a and miRNA-625-3p were down-regulated in the tumors compared to normal colonic mucosa. Significantly lower expression of both miRNAs was noticed in tumors with budding phenomenon compared to tumors without it (median values of miRNA-148a were 0.314 and 0.753 respectively, p = 0.011, and 0.404 and 0.620 respectively for miRNA-625-3p, p = 0.036). Significantly lower expression of miRNA-625-3p was detected in rectal tumors, compared to tumors in the colon (median 0.390 and 0.665 respectively, p = 0.037). Progression free survival was significantly lower in patients with high miRNA-148a expression (6 and 9 months respectively, p = 0.033), but there were no significant differences in PFS for miRNA-625-3p and in overall survival for both miRNAs.ConclusionsThere was a significant relationship between low miRNA-148a and miRNA-625-3p expression and tumor budding, which is thought to represent epithelial-mesenchymal transition. Both studied miRNAs may be associated with a more aggressive phenotype and could be the potential prognostic and predictive biomarkers in CRC. Further investigation is needed to confirm miRNAs involvement in EMT, and their prognostic and predictive value.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3575-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding

et al. 2017

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“…HTB has been demonstrated to independently affect disease-free survival and overall survival in colorectal cancers [12, 32], lung carcinomas [18, 19], and esophageal squamous cell carcinomas [13]. Moreover, HTB may serve as an additional prognostic factor to identify patients with stage I/II colorectal carcinoma at risk of recurrence following curative surgery [33, 34].…”

Section: Discussionmentioning

confidence: 99%

“…Morphologically, tumor budding is defined as the presence of single tumor cells or isolated small clusters of tumor cells (up to 5 tumor cells) scattered in the stroma at the invasive front; it represents a type of local diffusely infiltrative growth and occurs when tumor cells detach from the invasive tumor margin and migrate into the surrounding stroma. Tumor budding has frequently been observed in several types of solid tumors, including colorectal cancer [12], esophageal carcinoma [13], pancreatic carcinoma [14, 15], breast cancer [16, 17], lung carcinoma [18, 19], and endometrial carcinoma [20]; tumor budding has been recognized as an aggressive indicator and an adverse prognostic factor [12–20]. Moreover, as a result of its significant prognostic value, tumor budding is recommended by the International Union against Cancer for inclusion in the pathological report of colorectal cancer as an additional prognostic factor [21].…”

Section: Introductionmentioning

confidence: 99%

High-Grade Tumor Budding Stratifies Early-Stage Cervical Cancer with Recurrence Risk

Huang

Cai

et al. 2016

PLoS ONE

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ObjectivesThis study investigated prognostic significance of tumor budding in early-stage cervical cancer (ESCC) following radical surgery and its contribution to improve the stratification of patients with recurrence risk.MethodsThe archival medical records and H&E-stained slides of 643 patients with IA2-IIA stage cervical cancer who underwent radical surgery were retrospectively reviewed. Clinicopathological parameters were noted, and tumor buds were counted using immunohistochemistry for each case. The prognostic significance of tumor budding was analyzed. Prediction models that comprised tumor budding were established, and the performance was compared between the novel models and classic criteria via log-rank test and receiver operating characteristic analysis.ResultsTumors with high-grade tumor budding (HTB) exhibited a substantially increased risk of recurrence (hazard ratio = 4.287, P < 0.001). Nine predictive models for recurrence were established, in which HTB was combined with recognized risk factors. The model using of at least two risk factors of HTB, tumor size ≥ 4 cm, deep stromal invasion of outer 1/3, and lymphovascular space invasion to stratify patients with an intermediate risk was most predictive of recurrence compared with the classic criteria.ConclusionsTumor budding is an independent, unfavorable, prognostic factor for ESCC patients following radical surgery and holds promise for improved recurrence risk stratification.

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“…Tumor budding in CRC has been associated with poor disease outcomes in various studies (28). We divided our cohort into three groups based on tumor budding data; low (PBMC; n = 13, NILs/TILs; n = 11), intermediate (PBMC; n = 11, NILs/TILs; n = 7) and high (PBMC; n = 10, NILs/TILs; n = 9), and compared levels of various T cell subsets in circulation, NILs and TILs between them.…”

Section: Levels Of Cd4 + T Cells Are Similar In Patients Exhibiting Vmentioning

confidence: 99%

Immune Checkpoints in Circulating and Tumor-Infiltrating CD4+ T Cell Subsets in Colorectal Cancer Patients

et al. 2019

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Blockade of inhibitory immune checkpoints (ICs) is a promising therapeutic approach; however, it has shown limited success in some cancers including colorectal cancer (CRC). The tumor microenvironment (TME) is largely responsible for response to therapy, and its constituents may provide robust biomarkers for successful immunotherapeutic approaches. In this study, we performed phenotypical characterization and critical analyses of key inhibitory ICs and T regulatory cell (Treg)-related markers on CD4 + T cell subsets in CRC patients, and compared with normal colon tissues and peripheral blood from the same patients. We also investigated correlations between the levels of different CD4 + T cell subsets and the clinicopathologic features including disease stage and tumor budding. We found a significant increase in the levels of CD4 + FoxP3 + Helios + T cells, which represent potentially highly immunosuppressive Tregs, in the CRC TME. Additionally, tumor-infiltrating CD4 + T cells upregulated programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), T cell immunoglobulin and mucin domain-3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3). We also characterized the expression of PD-1, CTLA-4, TIM-3, and LAG-3 on different CD4 + FoxP3 −/+ Helios −/+ T cell subsets. Interestingly, we found that CTLA-4, TIM-3, and LAG-3 were mainly co-expressed on FoxP3 + Helios + Tregs in the TME. Additionally, FoxP3 high Tregs expressed higher levels of Helios, CTLA-4 and TIM-3 than FoxP3 low T cells. These results highlight the significance of Tregs in the CRC TME and suggest that Tregs may hamper response to IC blockade in CRC patients, but effects of different IC inhibition regimes on Treg levels or activity warrants further investigations. We also found that CD4 + CTLA-4 + T cells in circulation are increased in patients with advanced disease stage. This study simultaneously provides important insights into the differential levels of CD4 + T cell subpopulations and IC expression in CRC TME, compared to periphery and associations with clinicopathologic features, which could be used as potential biomarkers for CRC progression and response to therapy.

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Tumor Budding in Colorectal Carcinoma

Cited by 103 publications

References 36 publications

Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding

Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding

High-Grade Tumor Budding Stratifies Early-Stage Cervical Cancer with Recurrence Risk

Immune Checkpoints in Circulating and Tumor-Infiltrating CD4+ T Cell Subsets in Colorectal Cancer Patients

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