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New therapeutic targets are revolutionizing colorectal cancer clinical management, opening new horizons in metastatic patients' outcome. Polo Like Kinase1 (PLK1) inhibitors have high potential as antitumoral agents, however, the emergence of drug resistance is a major challenge for their use in clinical practice. Overcoming this challenge represents a hot topic in current drug discovery research. BI2536-resistant colorectal cancer cell lines HT29 R , RKO R , SW837 R and HCT116 R , were generated in vitro and validated by IG 50 assays and xenografts models by the T/C ratio. Exons 1 and 2 of PLK1 gene were sequenced by Sanger method. AXL pathway, Epithelial-to-Mesenchymal transition (EMT) and Multidrug Resistance (MDR1) were studied by qPCR and western blot in resistant cells. Simvastatin as a re-sensitizer drug was tested in vitro and the drug combination strategies were validated in vitro and in vivo. PLK1 gene mutation R136G was found for RKO R . AXL pathway trough TWIST1 transcription factor was identified as one of the mechanisms involved in HT29 R , SW837 R and HCT116 R lines, inducing EMT and upregulation of MDR1. Simvastatin was able to impair the mechanisms activated by adaptive resistance and its combination with BI2536 re-sensitized resistant cells in vitro and in vivo. Targeting the mevalonate pathway contributes to re-sensitizing BI2536-resistant cells in vitro and in vivo, raising as a new strategy for the clinical management of PLK1 inhibitors., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Tumor-infiltrating lymphocytes (TILs), mainly CD8 + cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium., Results: Here we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naïve and activated CD4 + and CD8 + T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4 + and CD8 + effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8 + T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2α-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-α4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8 + TIL density and disease-free survival. SOD3 expression was also linked to a T cell-inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program., Conclusion: Our findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically "cold" into "hot" tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8 + T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type-specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pancreatic adenocarcinoma upregulated factor (PAUF), also known as ZG16B, was previously found in the secretome of metastatic colorectal cancer cells. Here, we demonstrated the presence of PAUF at the intracellular level and its multiple effects on cancer progression. An initial decline of PAUF expression was observed at early stages of colorectal cancer followed by an increase at the metastatic site. PAUF was located at different cellular compartments: membrane-associated vesicles, endosomes, microtubule-associated vesicles, cell growth cones and the cell nucleus. PAUF loss in two colorectal cancer cell lines caused severe alterations in the cell phenotype and cell cycle, including tetraploidy, extensive genomic alterations, micronuclei and increased apoptosis. An exhaustive analysis of the PAUF interactome using different proteomic approaches revealed the presence of multiple components of the cell cycle, mitotic checkpoint, Wnt pathway and intracellular transport. Among the interacting proteins we found ZW10, a moonlighting protein with a dual function in membrane trafficking and mitosis. In addition, PAUF silencing was associated to APC loss and increased β-catenin nuclear expression. Altogether, our results suggest that PAUF depletion increases aneuploidy, promotes apoptosis and activates the Wnt/β-catenin pathway in colorectal cancer cells facilitating cancer progression. In summary, PAUF behaves as a multifunctional protein, with different roles in cancer progression according to the extra- or intracellular expression, suggesting a therapeutic value for colorectal cancer., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: Polo-like kinase 1 (Plk1) plays a key role in mitotic cell division and DNA damage repair. It has been observed that either up-regulated or down-regulated Plk1 could induce mitotic defects that results in aneuploidy and tumorigenesis, probably depending on the context. Few previous reports have associated Plk1 expression with prognosis and response to radiotherapy in rectal carcinomas. The aim of this study is to investigate the prognostic impact of Plk1 expression and its role in predicting response to neoadjuvant cheomoradiotherapy in rectal cancer., Methods and Results: Immunohistochemical analysis of Plk1 expression was performed in the pre-treatment tumour specimens from 75 rectal cancer patients. We analysed the assocation between Plk1 expression and clinicopathological parameters, pathologic response and outcome. Opposed to previous reports on this issue, low expression of Plk1 was significantly associated with a high grade of differentiation (P=0.0007) and higher rate of distant metastasis (P=0.014). More importantly, decreased levels of Plk1 were associated with absence of response after neoadjuvant therapy (P=0.049). Moreover, low Plk1 expression emerged as an unfavourable prognostic factor for disease-free survival in the non-responder group of patients (P=0.037)., Conclusions: Decreased Plk1 expression was associated with poor pathologic response and worse disease-free survival in rectal cancer patients receiving neoadjuvant chemoradiotherapy, suggesting Plk1 as a clinically relevant marker to predict chemoradiotherapy response and outcome., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Rectal cancer represents about 30% of colorectal cancers, being around 50% locally advanced at presentation. Chemoradiation (CRT) followed by total mesorectal excision is the standard of care for these locally advanced stages. However, it is not free of adverse effects and toxicity and the complete pathologic response rate is between 10% and 30%. This makes it extremely important to define factors that can predict response to this therapy. Focal adhesion kinase (FAK) expression has been correlated with worse prognosis in several tumours and its possible involvement in cancer radio- and chemosensitivity has been suggested; however, its role in rectal cancer has not been analysed yet. To analyse the association of FAK expression with tumour response to CRT in locally advanced rectal cancer. This study includes 73 patients with locally advanced rectal cancer receiving standard neoadjuvant CRT followed by total mesorectal excision. Focal adhesion kinase protein levels were immunohistochemically analysed in the pre-treatment biopsies of these patients and correlated with tumour response to CRT and patients survival. Low FAK expression was significantly correlated with local and distant recurrence (P = 0.013). Low FAK expression was found to be a predictive marker of tumour response to neoadjuvant therapy (P = 0.007) and patients whose tumours did not express FAK showed a strong association with lower disease-free survival (P = 0.01). Focal adhesion kinase expression predicts neoadjuvant CRT response in rectal cancer patients and it is a clinically relevant risk factor for local and distant recurrence., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Anemia is a frequent finding in patients with uremia due to chronic renal failure. Two factors contribute to the decrease in the red blood cell count and worsen the patient's general status: depression of erythropoiesis and shortening of the red blood cell lifespan., Case: A novel response mechanism to erythrocyte loss took place in a uremic patient with gastrointestinal hemorrhage. In an autopsy case of an 80-year-old woman dying of uremia, analysis of an intestinal fluid smear revealed small intestine epithelial cells engulfing complete erythrocytes., Conclusion: This cytologic finding could account for a potential response mechanism to counteract the massive erythrocyte loss that occurs in hemorrhagic anemia with a uremic background.