Cancer Biology: Foundations for Gastrointestinal Oncology Nursing Practice

Extracellular vehicles (EVs) are gaining increasing recognition as central contributors to the intricate landscape of the tumor microenvironment (TME). This manuscript provides an extensive examination of the multifaceted roles played by EVs in shaping the TME, with a particular emphasis on their involvement in metastasis, drug resistance, and immune evasion. Metastasis, the process by which cancer cells disseminate to distant sites, remains a formidable challenge in cancer management. EVs, encompassing exosomes and microvesicles, have emerged as critical participants in this cascade of events. They facilitate the epithelial-to-mesenchymal transition (EMT), foster pre-metastatic niche establishment, and enhance the invasive potential of cancer cells. This manuscript delves into the intricate molecular mechanisms underpinning these processes, underscoring the therapeutic potential of targeting EVs to impede metastasis. Drug resistance represents a persistent impediment to successful cancer treatment. EVs are instrumental in intrinsic and acquired drug resistance, acting as mediators of intercellular communication. They ferry molecules like miRNAs and proteins, which confer resistance to conventional chemotherapy and targeted therapies. This manuscript scrutinizes the diverse strategies employed by EVs in propagating drug resistance while also considering innovative approaches involving EV-based drug delivery systems to counteract this phenomenon. Immune evasion is a hallmark of cancer, and EVs are central in sculpting the immunosuppressive milieu of the TME. Tumor-derived EVs thwart immune responses through various mechanisms, including T cell dysfunction induction, the expansion of regulatory T cells (Tregs), and polarization of macrophages towards an immunosuppressive phenotype. In addition, the manuscript explores the diagnostic potential of EVs as biomarkers and their role as therapeutic agents in immune checkpoint blockade therapies. This manuscript provides a comprehensive overview of EV's pivotal role in mediating intricate interactions within the TME, ultimately influencing cancer progression and therapeutic outcomes. A profound understanding of EV-mediated processes in metastasis, drug resistance, and immune evasion opens up promising avenues for developing innovative therapeutic strategies and identifying valuable biomarkers in the ongoing battle against cancer.

Integrated molecular analysis demonstrated that colorectal cancer can be classified into four molecular subtypes (proliferative, immunomodulatory, immunosuppressed, and immune-excluded subtypes), providing valuable insight into the intricate relationship between tumor microenvironment heterogeneity and various clinical phenotypes.

Communication between EMT and PD-L1 signaling: New insights into tumor immune evasion.

Deciphering the changes in the tumor and tumor microenvironment (TME) that accompany metastatic disease progression is essential if we are to identify potential new anti-cancer treatments. In particular, a complete understanding of how cancer subclones and TME evolve over time from primary disease to death, both independently and in relation to one another, and of the impact of therapies such as immunotherapy (IO) on TME composition and architecture, remain lacking. In this work, we sought to profile the changes in both cancer-cell intrinsic genomic immune evasion and TME that accompany lung cancer progression from diagnosis to death. To do this, we applied multiple orthogonal methods (whole-exome sequencing; RNAseq; imaging mass cytometry) to >500 longitudinally collected primary, pre-mortem metastatic, and postmortem metastatic tumor samples from 23 patients with non-small cell lung cancer (NSCLC) co-recruited to the UK national TRACERx (TRAcking Cancer Evolution through therapy [Rx], NCT01888601) and PEACE (Posthumous Evaluation of Advanced Cancer Environment) autopsy studies. Samples covered multiple organ sites and were derived from both patients who did and did not receive IO, allowing analysis of the differential impact of treatment on end-stage disease profiles. Sequencing analyses suggest that heterogeneous mechanisms of immune evasion develop at distinct metastatic sites, and between metastases and the primary tumor. Profiling of TME indicated a global reduction in immune cell densities in metastatic compared to primary tumor samples and a skewing towards cytotoxic and terminally differentiated CD8 T cell subtypes. Previous work had identified four major TME architectures in primary NSCLC, based on the abundance and location of tumor infiltrating lymphocytes, macrophages and neutrophils, including a neutrophil-rich TME found to be associated with metastasis. In this work, we identified new TME classes found in metastatic samples, including those dominated by myeloid cells in the stroma. Two new TME classes, predominantly comprised of post-mortem metastatic samples from IO-treated patients, were significantly enriched in tumor-infiltrating cytotoxic CD8 T cells compared to other classes. TMEs of regions within the same metastasis were found to be more similar to each other than to those of primary tumor regions. Using computational approaches to track cancer subclones, we reconstructed metastatic migration histories for each patient and found that the TMEs of source and target metastases in a met-met migration pair were more similar than those from pairs of metastases from the same patient without a direct migration path. Our findings provide insights into the relationships between genetic immune evasion and immune cell infiltration across the lung cancer disease course. Citation Format: Sonya Hessey, Mihaela Angelova, Emma Colliver, Katey S. Enfield, Kerstin Haase, Michelle M. Leung, Corentin Richard, Robert Bentham, Clare Puttick, Oriol Pich, Wing Kin Liu, Alastair Magness, Abigail Bunkum, Kristiana Grigoriadis, Ariana Huebner, David A. Moore, Monica Sivakumar, Roberto Salgado, Philip S. Hobson, Dina Levi, Sophia Ward, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Andrew Rowan, Crispin T. Hiley, Simone Zaccaria, Nicholas McGranahan, Charles Swanton, Mariam Jamal-Hanjani. The evolution of immunity and immune evasion from early- to end-stage lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1207.

Prostate cancer (PCa) is considered immunologically cold with a tumor microenvironment (TME) that evades effective immune responses. PTEN loss and TMPRSS2-ERG fusion are common somatic mutations in PCa and both alterations have recently been suggested to impact TME immune infiltration. Interestingly, both mutations are considered to play a role in epithelial to mesenchymal transition (EMT). ZEB1, a stemness and EMT driver has also been associated with immune evasion in different types of tumors. In this study, we investigated the role of ZEB1 in the immune TME of prostate cancer and the putative cooperation between ZEB1 expression, PTEN loss and TMPRSS2-ERG fusion. Immunohistochemistry for PTEN, ERG and ZEB1 were analyzed in 43 PCa cases collected after radical prostatectomy, correlation analysis of expression and immune cell abundance prediction were accessed using PCa expression data from TCGA (n=494). Correlation analysis between ZEB1 expression and 395 genes involved in immune response showed a positive correlation with ERG (r=0.1941, P<0.0001), PTEN (r=0.3514, P<0.0001), STAT3 (r=0.3129, P<0.0001), BRCA2 (r=0.2381, P<0.0001), CSF1R (r=0.6041, P<0.0001), PDCD1 (r=0.2536, P<0.0001), CD274 (r=0.4044, P<0.0001), IL10 (r=0.3655, P<0.0001), IL2 (r=0.1973, P<0.0001), CCR7 (r=0.3325, P<0.0001) and CXCL8 (r=0.424, P<0.0001). When the cohort was dichotomized to compare fusion-positive to fusion-negative samples, ZEB1 correlation with ERG remained positive in fusion-negative samples (r=0.6422, P<0.0001) but was negative (r=-0.2147, P=0.0022) in fusion-positive samples. Immune cell abundance prediction showed a positive correlation between ZEB1 and Tregs (r=0.35, P<0.0001), monocytes (r=0.3874, P<0.0001), dendritic cells (r=0.3934, P<0.0001) and macrophages M1 (r=0.2176, P<0.0001) and a negative correlation with plasma cells (r=-0.2003, P<0.0001), CD8+ naïve T cells (r=-0.3565, P<0.0001), th1 cells (r=-0.4562, P<0.0001) and pro B-cells (r=-0.3539, P<0.0001). Immunohistochemistry analysis showed a high expression of ZEB1 in non-neoplastic basal epithelium plus variable intensitiy of expression in adenocarcinomas and corroborated the correlation between ZEB1, PTEN and ERG expression levels. ZEB1 correlation with immunosuppressive cytokines and receptors such as CCR7, IL2, IL10, IL8 and PD-L1 provides evidence that ZEB1 and EMT may play an immune evasive role in PCa. The positive correlation with Tregs also supports this putative role. ZEB1 expression may indicate that stemness is associated with activation of downstream pathways modulated by PTEN and ERG. The correlation with BRCA2 may indicate an increased stemness-related role for this DNA damage response pathway. These observations, and our IHC findings, are in agreement with recently published data showing that ZEB1 is critical to a subset of basal stem cells in murine prostate samples. Citation Format: Luiz P. Chaves, Andre L. Caliari, Camila M. Melo, Fabiano P. Saggioro, Jeremy A. Squire. ZEB1 expression is associated with the PTEN loss and TMPRSS2 ERG fusion immune evasion phenotype in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1818.

It is increasingly appreciated that host factors within the tumor center and microenvironment play a key role in dictating colorectal cancer (CRC) outcomes. As a result, the metastatic process has now been defined as a result of epithelial-mesenchymal transition (EMT). Establishment of the role of EMT within the tumor center and its effect on the tumor microenvironment would be beneficial for prognosis and therapeutic intervention in CRC. The present study assessed five immunohistochemical EMT markers within the tumor center on a 185 Stage II/III CRC patient tissue microarray. In 185 patients with CRC, cytoplasmic snail (HR 1.94 95% confidence interval [CI] 1.15-3.29, p = 0.012) and a novel combined EMT score (HR 3.86 95% CI 2.17-6.86, p < 0.001) were associated with decreased cancer-specific survival. The combined EMT score was also associated with increased tumor budding (p = 0.046), and systemic inflammation (p = 0.007), as well as decreased memory T-cells within the stroma (p = 0.030) and at the invasive margin (p = 0.035). Furthermore, the combined EMT score was associated with cancer-specific survival independent of TNM-stage (HR 4.12 95% CI 2.30-7.39, p < 0.001). In conclusion, a novel combined EMT score stratifies patient's survival in Stage II/III CRC and associates with key factors of tumor metastasis. Therefore, the combined EMT score could be used to identify patients at risk of micrometastases and who may benefit from standard adjuvant therapy, potentially in combination with EMT blockade.

NG03: Marine omega-3 polyunsaturated fatty acid and colorectal cancer prevention and treatment

Simple SummaryIntratumoral heterogeneity is considered the major cause of drug resistance and hence treatment failure in cancer patients. Tumor cells are known for their phenotypic plasticity that is the ability of a cell to reprogram and change its identity to eventually adopt multiple phenotypes. Tumor cell plasticity involves the reactivation of developmental programs, the acquisition of cancer stem cell properties and an enhanced potential for retro- or transdifferentiation. A well-known transdifferentiation mechanism is the process of epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and various signals from the tumor microenvironment (TME) in shaping a tumor cell’s plasticity. The vulnerabilities exposed by cancer cells when residing in a plastic or stem-like state have the potential to be exploited therapeutically, i.e., by converting highly metastatic cells into less aggressive or even harmless postmitotic ones.Intratumoral heterogeneity is considered the major cause of drug unresponsiveness in cancer and accumulating evidence implicates non-mutational resistance mechanisms rather than genetic mutations in its development. These non-mutational processes are largely driven by phenotypic plasticity, which is defined as the ability of a cell to reprogram and change its identity (phenotype switching). Tumor cell plasticity is characterized by the reactivation of developmental programs that are closely correlated with the acquisition of cancer stem cell properties and an enhanced potential for retrodifferentiation or transdifferentiation. A well-studied mechanism of phenotypic plasticity is the epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and clues from the tumor microenvironment in cell reprogramming. A deeper understanding of the connections between stem cell, epithelial–mesenchymal, and tumor-associated reprogramming events is crucial to develop novel therapies that mitigate cell plasticity and minimize the evolution of tumor heterogeneity, and hence drug resistance. Alternatively, vulnerabilities exposed by tumor cells when residing in a plastic or stem-like state may be exploited therapeutically, i.e., by converting them into less aggressive or even postmitotic cells. Tumor cell plasticity thus presents a new paradigm for understanding a cancer’s resistance to therapy and deciphering its underlying mechanisms.

Highlights from Recent Cancer Literature

Colorectal cancers (CRC) displaying DNA microsatellite instability (MSI) are associated with a favorable natural history, but the molecular basis for this observation has not been defined. We sought to determine whether the epithelial-to-mesenchymal transition (EMT), a highly conserved process involved in embryogenesis as well as in tumor progression, invasion, and metastasis, is impaired in MSI-positive CRCs that characteristically have a mutant transforming growth factor-β receptor type II (TGFBR2) gene. The induction of EMT by TGF-β1 was analyzed by phase contrast microscopy, immunofluorescence, qRT-PCR, immunoblotting, and cellular migration and invasion assays in MSS (SW480 and HT29) and MSI (DLD1 and HCT116) colon cancer cell lines. Expression of epithelial (E-cadherin) and mesenchymal (vimentin and N-cadherin) markers was evaluated by immunohistochemistry and qRT-PCR in 129 human colorectal tumors. TGF-β1 induced changes in cellular morphology from an epithelial to a fibroblasticlike morphology, changes in gene and protein expression with a reduction in E-cadherin and induction of vimentin, and changes in motility and invasion consistent with the occurrence of EMT only in MSS colon cancer cells. These effects did not require Smad4 but depended upon the recruitment of ERK. Cells with MSI and mutant TGFBR2 failed to exhibit any of these changes in response to TGF-β1. However, tumor cells with MSI but wildtype TGFBR2 underwent EMT in response to TGF-β1, indicating that TGFBR2 genotype is a key determinant of the EMT response in tumors with MSI. In human colorectal tumors, expression of the EMT markers N-cadherin and vimentin was significantly associated with adverse clinicopathologic features and the absence of MSI. These findings define a unique genotype-phenotype relationship between TGFBR2 and EMT that may contribute to the improved prognosis consistently observed in colon cancers with MSI. Furthermore, these results suggest a potential rationale for the therapeutic inhibition of TGF-β signaling in MSS colorectal tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B115.

Immune evasion-a well-established cancer hallmark-is a major barrier to immunotherapy efficacy. While the molecular mechanisms and biological consequences underpinning immune evasion are largely known, the role of tissue mechanical stresses in these processes warrants further investigation. The tumor microenvironment (TME) features physical abnormalities (notably, increased fluid and solid pressures applied both inside and outside the TME) that drive cancer mechanopathologies. Strikingly, in response to these mechanical stresses, cancer cells upregulate canonical immune evasion mechanisms, including epithelial-mesenchymal transition (EMT) and autophagy. Consideration and characterization of the origins and consequences of tumor mechanical stresses in the TME may yield novel strategies to combat immunotherapy resistance. In this Perspective, we posit that tumor mechanical stresses-namely fluid shear and solid stresses-induce immune evasion by upregulating EMT and autophagy. In addition to exploring the basis for our hypothesis, we also identify explicit gaps in the field that need to be addressed in order to directly demonstrate the existence and importance of this biophysical relationship. Finally, we propose that reducing or neutralizing fluid shear stress and solid stress-induced cancer immune escape may improve immunotherapy outcomes.

BackgroundStomach adenocarcinoma (STAD) with microsatellite instability (MSI) is associated with a better prognosis compared to Non-MSI. This study aims to elucidate the differences in the tumor microenvironment (TME) of MSI and explore its underlying mechanisms in STAD.MethodsTME differences between MSI and Non-MSI were analyzed using single-cell RNA sequencing (MSI = 7, Non-MSI = 19) and bulk RNA sequencing (MSI = 39, Non-MSI = 198). Differentially expressed genes (DEGs) were used to identify enriched pathways and hub genes. TNFSF9 expression was validated by immunohistochemistry (IHC) on 23 STAD sections (MSI = 13, Non-MSI = 10) and confirmed in tumor epithelial cells using SNU-1 (MSI) and AGS (Non-MSI) cell lines through quantitative polymerase chain reaction (qPCR) and Western blot (WB).ResultsThe results showed MSI was significantly associated with a better prognosis (P < 0.05). Within the TME, MSI was associated with a higher abundance of antigen-presenting cells, including M1 macrophages (40.1% vs. 27.9%) and activated dendritic cells (22.1% vs. 10.5%), as well as pro-inflammatory Th1-like CD4⁺ T cells (15% vs. 11%). However, MSI also showed an increase in exhausted T cells, indicating a complex immune landscape. Signaling pathway and cell communication analyses revealed an enrichment of cytokine-related pathways in MSI. Hub gene analysis revealed that TNFSF9 was predominantly expressed in stromal cells and partially in tumor epithelial cells in MSI, with its upregulation further confirmed through IHC, qPCR, and WB. Correlation analysis demonstrated a positive relationship between TNFSF9 expression and the abundance of M1 macrophages.ConclusionsThese findings provide new insights into the TME of MSI in STAD, emphasizing the significant role of TNFSF9 in shaping MSI-specific TME, enhancing immunotherapy efficacy, and improving patient survival.

Extracellular vesicle-mediated transport: Reprogramming a tumor microenvironment conducive with breast cancer progression and metastasis

Immune evasion and epithelial-mesenchymal transition (EMT) are critical mechanisms driving tumor progression and therapy resistance in prostate cancer. In this study, we explored the role of TDP2 in modulating the tumor microenvironment (TME) through single-cell RNA sequencing and pathway enrichment analysis. Our results revealed that epithelial cells with high TDP2 expression extensively interact with myeloid cells, macrophages, and fibroblasts, thereby shaping immune responses and facilitating tumor progression. Specifically, TDP2 overexpression suppressed M1 macrophage polarization and dendritic cell (DC) maturation, leading to reduced CD8 + T cell activation and enhanced immune evasion. Additionally, TDP2-high expression was associated with enriched signaling pathways involved in EMT, including COLLAGEN, GALECTIN, MIDKINE (MK), and ONCOSTATIN M (OSM), which promoted tumor cell migration, invasion, and immune evasion. Survival analyses further demonstrated that high TDP2 expression correlated with poor clinical outcomes in prostate cancer patients. Overall, our findings identify TDP2 as a key regulator within the TME and suggest its potential utility as both a prognostic biomarker and therapeutic target in prostate cancer.

Immune evasion and epithelial-mesenchymal transition (EMT) are critical mechanisms driving tumor progression and therapy resistance in prostate cancer. In this study, we explored the role of TDP2 in modulating the tumor microenvironment (TME) through single-cell RNA sequencing and pathway enrichment analysis. Our results revealed that epithelial cells with high TDP2 expression extensively interact with myeloid cells, macrophages, and fibroblasts, thereby shaping immune responses and facilitating tumor progression. Specifically, TDP2 overexpression suppressed M1 macrophage polarization and dendritic cell (DC) maturation, leading to reduced CD8 + T cell activation and enhanced immune evasion. Additionally, TDP2-high expression was associated with enriched signaling pathways involved in EMT, including COLLAGEN, GALECTIN, MIDKINE (MK), and ONCOSTATIN M (OSM), which promoted tumor cell migration, invasion, and immune evasion. Survival analyses further demonstrated that high TDP2 expression correlated with poor clinical outcomes in prostate cancer patients. Overall, our findings identify TDP2 as a key regulator within the TME and suggest its potential utility as both a prognostic biomarker and therapeutic target in prostate cancer.