Colorectal cancer liver metastasis histological growth patterns; the role of the immune system
Bibliographic record
Abstract
Background: Colorectal cancer (CRC) is amongst the three most common cancers worldwide. The majority of patients presenting with liver metastases (LM). Resection of liver lesions is the only curative measure. Unfortunately, less than 30% of patients are eligible for resection. Three major histological growth patterns (HGPs) have been identified in patients with colorectal cancer liver metastasis (CRCLM); desmoplastic, pushing and replacement. Patients with replacement lesions have a poor overall survival rate compared to those with desmoplastic when treated. A number of studies have reported that the magnitude of T-lymphocyte infiltration in CRCLM is significantly correlated with prognosis. High infiltration of macrophages has also been associated with better outcome. Furthermore, the role of these immune components when LM are segregated by HGP has not yet been evaluated thoroughly. Defining this is important in light of the fact that new therapies are based on manipulation of various components of the immune system. Methodology Gene Expression Analysis: Samples were obtained through the McGill University Hospital Centre Liver Disease Biobank; 9 Desmoplastic and 7 Replacement lesions. To minimize heterogeneity in the data, we selected chemonaïve samples. Samples were scored with our pathologist collaborators. Tumors were macrodissected, along with adjacent normal liver and processed Sequencing was performed by our collaborator Dr. Woong-Yang Park at the Samsung Genome Centre in South Korea, using the illumine HISeq sequencers. R© software was used to identify differentially expressed genes, and to generate heatmaps. From the output data, we studyied genes and pathways using Ingenuity Pathway Analysis © software.Immune Cell Quantification: Serial sections of formalin fixed paraffin embedded biopsies from CRCLM of both desmoplastic and replacement HGPs were stained via immunofluorescence, to assess the presence and distribution of various subtypes of T-lymphocytes and macrophages. Antibodies used were: CD68 (all macrophages), IRF5 (M1 macrophages), CMAF (M2 macrophages). Granzyme B (activated cytotoxic T-lymphocytes), CD4 (helper T-lymphocytes), and FOXP3 (regulatory T-lymphocytes). Tiled images of the whole tissue sections were obtained using a florescent microscope, followed by manual counting of each of the immune cell populations.ResultsGene Expression Analysis: Significant biological functions between the patterns consisted of those mostly related to cellular processes such as survival and invasion, suggesting that genes differentially expressed are those related to the tumor formation and metastases cascade. Furthermore, various genes that are related to immunological functions are mostly activated in the replacement pattern and conversely undetected in the desmoplastic subtypes.Immune Cell Quantification: The majority of immune cell populations concentrated at the tumor/liver interface in both growth patterns, whether that be the tumor peripheries, the desmoplastic ring, or the adjacent normal livers. Furthermore, when comparing desmoplastic and replacement patterns, we found that immune cells are mostly higher at the tumor/liver interface of the replacement pattern. We have also identified a rare subtype of immune cells; CD4- regulatory T-lymphocytes. This population has not yet been described in patients with CRC or with CRCLM.Conclusions: Different components of the immune system play diverse roles in the desmoplastic and replacement patterns of CRCLM. The findings described in this paper are new and will help increase our understanding of the diversity of CRC liver metastases. Such findings can direct future work to identity new prognostic markers and to help future therapeutics development towards therapies that can manipulate various components of the immune system.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".