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Our aim was to determine factors predictive of long-term post-gastrectomy outcomes in older adults with pathological stage I gastric cancer (GC). A total of 175 patients with resected pathological stage I GC at two institutions were reviewed, each ≥75 years old at the time of gastrectomy and full participants in a 5-year follow-up program. The procedures were undertaken between January 2006 and December 2011. Patients were divided into two groups: survivors and non-survivors at postoperative Year 5. Univariate and multivariate analyses were applied to identify independent predictors of 5-years survival, including preoperative, surgical, and histopathologic variables. Multivariate analysis of overall survival (OS) at 5 years indicated that prognostic nutritional index (PNI) <45 and the American Society of Anesthesiologists physical status (ASA-PS) 3 were independently associated with unfavorable outcomes. A clinical score consisting of 1-point each for these two variables proved useful in predicting survival after gastrectomy (5-year OS: 0 point, 86.6%; 1-point, 51.6%; 2-point, 33.3%; p <.001, area under the curve [AUC] = 0.757). Long-term survival of older adults with pathological stage I GC is unfavorable in patients displaying both ASA-PS 3 and PNI < 45. A simple scoring method, based on combined ASA-PS/PNI determinations, provides an accurate prognostic prediction for these patients. [ABSTRACT FROM AUTHOR]

Background: Patients with overweight reportedly have more comorbidities, including diabetes mellitus and cardiovascular disease, and longer operating times as well as more blood loss during surgery compared with those with normal weight. However, the impact of overweight on the short-term outcome after transthoracic esophagectomy for patients with esophageal squamous cell carcinoma (ESCC) remains unclear. We hypothesized that overweight has a negative impact on short-term surgical outcomes after esophagectomy for patients with ESCC. Methods: A total of 304 patients who underwent transthoracic esophagectomy for ESCC were included in this study. Body mass index (BMI) was classified into three categories, <18.49, 18.50-24.99, and >25.00 (kg/m), defined as low, normal, and high BMI, respectively, according to the World Health Organization criteria. We investigated the association of BMI status with patient demographics and surgical outcomes after esophagectomy for patients with ESCC. In addition, overall survival and relapse-free survival stratified by BMI were compared. Results: Fifty-nine (19.4 %) and 41 (13.4 %) patients were classified to low BMI and high BMI, respectively. The high-BMI group had significantly higher comorbidity rates of diabetes mellitus ( p < 0.01) and anastomotic leakage ( p = 0.011) than the normal-BMI group. There were no significant association between high BMI and another various complications except for an anastomotic leakage, severe complications defined by Clavien-Dindo classification and in-hospital mortality. In multivariate analysis, high BMI was a significant risk factor for anastomotic leakage ( p = 0.030, hazard ratio; 3.423, 95%CI; 1.128-10.38). On the other hand, no significant association was observed between low BMI and short surgical outcomes. There were no significant differences in overall and relapse-free survival among the three BMI groups in univariate and multivariate analysis ( p = 0.128 and p = 0.584, respectively). Conclusion: The surgical treatment should not be denied for patients with ESCC due to overweight and underweight. However, intraoperative prevention and postoperative careful monitoring for anastomotic leakage might be required after esophagectomy for overweight patients with ESCC. [ABSTRACT FROM AUTHOR]

The aim of this study was to clarify the role of fibroblast-derived Lysyl oxidase-like 2 (LOXL2) in the development of gastric cancer. The correlation between the clinicopathological features of 548 primary gastric carcinomas and LOXL2 expression in stromal cells was examined by immunohistochemistry. Two gastric cancer cell lines, OCUM-12 and NUGC-3, and cancer-associated fibroblasts (CAFs) were used in this in vitro study. The effect of fibroblast-derived LOXL2 on the motility of gastric cancer cells was analyzed by using a wound-healing assay, a double-chamber invasion assay, and western blot. LOXL2 expression in stromal cells was significantly associated with tumor invasion depth, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal dissemination. Multivariable logistic regression analysis revealed that LOXL2 expression in stromal cells could be an independent predictive parameter for the overall survival of patients. CAFs significantly stimulated the migration and invasion of OCUM-12 and NUGC-3 cells. This motility-stimulating ability of CAFs was inhibited by LOXL2 siRNA. Western blot analysis indicated that phosphorylation of focal adhesion kinase (FAK) in cancer cells was increased by the conditioned medium from CAFs, and was decreased by the conditioned medium from LOXL2 siRNA-treated CAFs. LOXL2 expression in stromal cells may be a useful prognostic factor for patients with gastric cancer. Fibroblast-derived LOXL2 may stimulate the motility of gastric cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The aim of this study was to clarify the ability of a FGFR2 inhibitor, Ki23057, to enhance the chemosensitivity of drug-resistant gastric cancer cell lines when used in combination with chemotherapeutic drugs. Materials and methods: Five cancer cell lines resistant to irinotecan (SN38), paclitaxel (PTX), etoposide (VP16), oxaliplatin (OXA), and gemcitabine (GEM) were respectively established from a parent gastric cancer cell line, OCUM-2M, and were named OCUM-2M/SN38, OCUM-2M/PTX, OCUM-2M/VP16, OCUM-2M/OXA, and OCUM-2M/GEM. The effects of the combination of Ki23057 with anticancer drugs on proliferation, apoptosis, and mRNA expression were examined. Results: Ki23057 significantly decreased the IC50 values of OCUM-2M/SN38, OCUM-2M/PTX, and OCUM-2M/VP16, but not those of OCUM-2M/OXA and OCUM-2M/GEM. Ki23057 significantly enhanced the apoptosis rates induced by chemotherapeutic drugs in both the drug-resistant cell lines and the parental cell line. Ki23057 decreased the ERCC1 expression level in OCUM-2M/SN38, OCUM-2M/PTX, and OCUM-2M/VP16. Ki23057 increased the p53 expression level in OCUM-2M/SN38 and OCUM-2M/PTX, but not in OCUM-2M/VP16. Conclusion: The FGFR2 inhibitor Ki23057 might be therapeutically promising for treating drug-resistant gastric cancer cells, especially when used in combination with SN38, PTX, or VP16. The apoptosis process might be the main mechanism underlying the synergistic effect of these combinations. The ERCC1 and p53 genes may play an integral role in the synergism between Ki23057 and chemotherapeutic agents in drug-resistant cell lines. [Copyright &y& Elsevier]

Gastric cancer cells leaving the primary tumour are exposed to low oxygen levels in the peritoneal cavity; however, peritoneal metastatic phenotypes of hypoxic cancer cells remain unclear. We used 6 gastric cancer cell lines, including 3 diffuse-type gastric cancer (DGC) and 3 non-DGC cell lines. Using adhesion assay, we examined the effect of hypoxic conditions on their ability to adhere to peritoneal components. The expression level of transforming growth factor-β (TGF-β) and integrins mRNA of cancer cells was examined using reverse transcriptase-polymerase chain reaction. We further examined the effect of anti-integrin neutralising antibodies and a TGF-β receptor inhibitor on the adhesion ability of hypoxic cancer cells. The binding ability of DGC cells was higher than that of non-DGC cells; it was significantly increased by hypoxic (1% O2) conditions compared to normoxic (21% O2) conditions. In contrast, no remarkable change in adhesion ability was observed in the non-DGC cells under normoxic and hypoxic conditions. Integrins and TGF-β expression of hypoxic DGC cells was significantly higher than that of normoxic cells. TGF-β increased the adhesion ability and α2-, α3- and α5-integrin expression of hypoxic DGC cells, whereas the TGF-β receptor inhibitor decreased them. Neutralising antibodies against α2-, α3- and α5-integrin inhibited the adhesion ability of DGC cells. These findings suggested that hypoxic conditions promote the adhesion of DGC cells to the peritoneum. The upregulation of α2-, α3- and α5-integrin by TGF-β under hypoxic conditions may be one of the mechanisms responsible for the high metastatic potential of hypoxic DGC cells to the peritoneum. [Copyright &y& Elsevier]

Abstract: An inhibitory-effect of a selective cyclooxygenase-2 (COX-2) inhibitor on peritoneal metastasis of scirrhous gastric carcinoma was investigated in vivo. Peritoneal metastasis had developed after intraperitoneal inoculation of scirrhous gastric cancer cells, OCUM-2MD3, in nude mice. COX-2 inhibitor and/or S-1 were administered orally in nude mice with peritoneal metastasis. Oral administration of COX-2 inhibitor and S-1 significantly prolonged survival rates of these nude mice, compared with either alone. These findings suggested that combining S-1 and COX-2 inhibitor administration obtain a synergistic inhibitory-effect on the peritoneal metastasis of scirrhous gastric carcinoma. [Copyright &y& Elsevier]

Background & Aims: Scirrhous gastric carcinoma carries the highest mortality of all gastric cancers. The poor prognosis is reported to be associated with K-samII amplification, which encodes fibroblast growth factor receptor type 2 (FGF-R2). Ki23057, a newly developed small molecule-acting K-samII/FGF-R2 autophosphorylation inhibitor, is a tyrosine kinase inhibitor that competes with adenosine triphosphate for the binding site. The aim of the current study is to clarify the possibility of molecular target therapy with Ki23057 for treating scirrhous gastric cancer. Methods: Five human gastric cancer cell lines were used. OCUM-2MD3 and OCUM-8 were derived from scirrhous carcinomas. MKN-7, MKN-45, and MKN-74 cells were derived from nonscirrhous carcinomas. In vitro effects of Ki23057 on cell growth were determined by calculating the number of cancer cells. The influences of Ki23057 on the mitogen-activated protein kinase and phosphatidylinositol 3 kinase signaling pathways and the apoptosis pathway in the gastric cancer cells were also examined. For in vivo experiments, the Ki23057 was administered orally to mouse models of peritoneal dissemination. Results: K-samII amplification was found in OCUM-2MD3 and OCUM-8 cells but not in MKN-7, MKN-45, or MKN-74 cells. Ki23057 significantly inhibited the proliferation of scirrhous cancer cells but not nonscirrhous gastric carcinoma cells. Ki23057 decreased phosphorylation of K-samII/FGF-R2, extracellular signal-regulated kinase, and Akt and increased apoptosis in scirrhous cancer lines. The oral Ki23057 administration significantly (P < .001) prolonged survival of mice with peritoneal dissemination following injection of OCUM-2MD3 scirrhous cancer cells. Conclusions: A novel K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, appears therapeutically promising in scirrhous gastric carcinoma with K-samII amplification. [Copyright &y& Elsevier]

Abstract: Desmoglein-2 (Dsg2) is one of the components of the cell–cell adherence junction. We previously reported that loss of heterozygosity at chromosome 18q12, on which the Dsg2 gene exists, is frequently found in diffuse-type gastric cancers. This study investigated the relationship between Dsg2 expression and diffuse-type gastric cancers. A total of 112 primary tumours resected from patients with gastric cancer were stained with a monoclonal antibody against Dsg2 and examined for correlations between the expression of Dsg2 and various clinicopathological factors, including loss of heterozygosity on chromosome 18q and prognosis. Dsg2 is immunolocalised at cell–cell boundaries in normal gastric mucosa. Loss of Dsg2 expression was observed in 33 of 112 gastric tumours. There was a statistically significant correlation between a decrease in Dsg2 staining and loss of tumour differentiation (P <0.001), tumour macroscopic feature (P <0.001) and peritoneal dissemination (P =0.023), and Dsg2-negative staining was correlated significantly with loss of heterozygosity on chromosome 18q12 (P =0.001). The prognosis of patients with Dsg2-negative tumours was significantly worse than that of those with Dsg2-positive tumours (log rank, P <0.01), while multivariate analysis revealed that Dsg2 was not an independent prognostic factor. These findings suggest that decreased expression of Dsg2 is associated with diffuse-type gastric cancers and poor prognosis in gastric carcinoma. [Copyright &y& Elsevier]

Background & Aims Fibroblasts that interact with cancer cells are called cancer-associated fibroblasts (CAFs), which promote progression of different tumor types. We investigated the characteristics and functions of CAFs in diffuse-type gastric cancers (DGCs) by analyzing features of their genome and gene expression patterns. Methods We isolated CAFs and adjacent non-cancer fibroblasts (NFs) from 110 gastric cancer (GC) tissues from patients who underwent gastrectomy in Japan from 2008 through 2016. Cells were identified using specific markers of various cell types by immunoblot and flow cytometry. We selected pairs of CAFs and NFs for whole-exome and RNA sequencing analyses, and compared expression of specific genes using quantitative reverse transcription PCR. Protein levels and phosphorylation were compared by immunoblot and immunofluorescence analyses. Rhomboid 5 homolog 2 (RHBDF2) was overexpressed from a transgene in fibroblasts or knocked down using small interfering RNAs. Motility and invasiveness of isolated fibroblasts and GC cell lines (AGS, KATOIII, MKN45, NUGC3, NUGC4, OCUM-2MD3 and OCUM-12 cell lines) were quantified by real-time imaging analyses. We analyzed 7 independent sets of DNA microarray data from patients with GC and associated expression levels of specific genes with patient survival times. Nude mice were given injections of OCUM-2MD3 in the stomach wall; tumors and metastases were collected and analyzed by immunohistochemistry. Results Many of the genes with increased expression in CAFs compared with NFs were associated with transforming growth factor beta 1 (TGFB1) activity. When CAFs were cultured in extracellular matrix, they became more motile than NFs; DGC cells incubated with CAFs were also more motile and invasive in vitro than DGC cells not incubated with CAFs. When injected into nude mice, CAF-incubated DGC cells invaded a greater number of lymphatic vessels than NF-incubated DGC cells. We identified RHBDF2 as a gene overexpressed in CAFs compared with NFs. Knockdown of RHBDF2 in CAFs reduced their elongation and motility in response to TGFB1, whereas overexpression of RHBDF2 in NFs increased their motility in extracellular matrix. RHBDF2 appeared to regulate oncogenic and non-canonical TGFB1 signaling. Knockdown of RHBDF2 in CAFs reduced cleavage of the TGFB receptor 1 (TGFBR1) by ADAM metallopeptidase domain 17 (ADAM17 or TACE) and reduced expression of genes that regulate motility. Incubation of NFs with in interleukin 1 alpha (IL1A), IL1B or tumor necrosis factor, secreted by DGCs, increased fibroblast expression of RHBDF2. Simultaneous high expression of these cytokines in GC samples was associated with shorter survival times of patients. Conclusions In CAFs isolated from human DGCs, we observed increased expression of RHBDF2, which regulates TGFB1 signaling. Expression of RHBDF2 in fibroblasts is induced by inflammatory cytokines (such as IL1A, IL1B, and tumor necrosis factor) secreted by DGCs. RHBDF2 promotes cleavage of TGFBR1 by activating TACE and motility of CAFs in response to TGFB1. These highly motile CAFs induce DGCs to invade extracellular matrix and lymphatic vessels in nude mice. [ABSTRACT FROM AUTHOR]

Heat shock protein 72 (Hsp72) is a molecular chaperone that assists in the folding of nascent polypeptides and in the refolding of denatured proteins. In many cancers, Hsp72 is constitutively expressed at elevated levels, which can result in enhanced stress tolerance. Similarly, following treatment with anticancer drugs, Hsp72 binds to denatured proteins that may be essential for survival. We therefore hypothesized that Hsp72 client proteins may play a crucial role in drug resistance. Here, we aimed to identify proteins that are critical for oxaliplatin (OXA) resistance by analyzing human gastric cancer cell lines, as well as OXA-resistant cells via a mass spectrometry-based proteomic approach combined with affinity purification using anti-Hsp72 antibodies. Stromal cell-derived factor 2 (SDF-2) was identified as an Hsp72 client protein unique to OCUM-2M/OXA cells. SDF-2 was overexpressed in OXA-resistant cells and SDF-2 silencing promoted the apoptotic effects of OXA. Furthermore, Hsp72 prevented SDF-2 degradation in a chaperone activity-dependent manner. Together, our data demonstrate that Hsp72 protected SDF-2 to avoid OXA-induced cell death. We propose that inhibition of SDF-2 may comprise a novel therapeutic strategy to counteract OXA-resistant cancers. [ABSTRACT FROM AUTHOR]

Diffuse-type gastric carcinoma (DGC) has a poor prognosis due to its rapid diffusive infiltration and frequent peritoneal dissemination. DGC is associated with massive fibrosis caused by aberrant proliferation of cancer-associated fibroblasts (CAFs). Previously, we reported that direct heterocellular interaction between cancer cells and CAFs is important for the peritoneal dissemination of DGC. In this study, we aimed to identify and target the molecules that mediate such heterocellular interactions. Monoclonal antibodies (mAbs) against intact DGC cells were generated and subjected to high-throughput screening to obtain several mAbs that inhibit the adhesion of DGC cells to CAFs. Immunoprecipitation and mass spectrometry revealed that all mAbs recognized integrin α5 complexed with integrin β1. Blocking integrin α5 in DGC cells or fibronectin, a ligand of integrin α5β1, deposited on CAFs abrogated the heterocellular interaction. Administration of mAbs or knockout of integrin α5 in DGC cells suppressed their invasion led by CAFs in vitro and peritoneal dissemination in a mouse xenograft model. Altogether, these findings demonstrate that integrin α5 mediates the heterotypic cancer cell-fibroblast interaction during peritoneal dissemination of DGC and may thus be a therapeutic target. [ABSTRACT FROM AUTHOR]

Peritoneal metastasis of gastric cancer (GC) results in extremely poor prognoses. The peritoneal cavity is covered by a monolayer of peritoneal mesothelial cells (PMCs). Interactions between GC cells and PMCs might play a pivotal role in peritoneal metastasis. Extracellular vesicles (EVs) correlate with intercellular communication. Although intercellular communication between cancer cells and PMCs might be associated with the peritoneal metastatic process, the role of EVs from PMCs remains unclear. We investigated the effects of EVs from PMCs on GC cells. Three GC cell lines (OCUM-12, NUGC-3, and MKN74) and four mesothelial cell lines were used. The effects of EVs derived from the PMCs on the invasion and migration of GC cells were evaluated by Matrigel invasion assay. Factors contained in the PMC EVs were analyzed; extra-cellular matrix metalloproteinase inducer (EMMPRIN) was detected in the EVs. The effects of an EMMPRIN inhibitor on the invasion-stimulating activity of EVs were examined. The EMMPRIN expressions of 110 GCs were evaluated by immunohistochemistry. PMC EVs significantly promoted the invasion of diffuse-type GC cells, i.e., OCUM-12 and NUGC-3 cells. EMMPRIN in the EVs stimulated the invasion of OCUM-12 and NUGC-3 cells. The invasion-stimulating activity of PMC EVs was inhibited by the EMMPRIN inhibitor. A high EMMPRIN expression in PMCs was significantly associated with worse cancer-specific survival and peritoneal-recurrence-free survival. EMMPRIN in EVs from PMCs might stimulate the malignant progression of diffuse-type GC. EMMPRIN might be a useful prognostic marker of recurrence in GC patients. [ABSTRACT FROM AUTHOR]

Abstract: Ki23057 is a new, small synthetic tyrosine kinase inhibitor that blocks autophosphorylation of the VEGF receptor2 (VEGFR2). To determine the effect of Ki23057 as an anti-angiogenic agent, we studied the effect of Ki23057 for colon cancer and vascular endothelial cells in vitro and in vivo. Ki23057 inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs), whereas no inhibitory effect of Ki23057 on the proliferation of three colon cancer cells (LM-H3, LoVo and LS174T) was observed by means of the cell count assay. Ki23057 inhibited tube formation of HUVECs. Immunoprecipitation demonstrated that Ki23057 inhibited tyrosine phosphorylation of VEGFR2 in HUVECs. Ki23057 exhibited a significant inhibitory effect on the growth of the xenografted LM-H3 tumours and the spreading of cancer cells to the liver. Anti-CD31 antibody stained significantly fewer microvessels in the xenografted tumours treated with Ki23057 compared with controls. Ki23057 may be a promising new antiangiogenic agent for colon cancer. [Copyright &y& Elsevier]

Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8+ T cells excluded to the stromal periphery, resistant to immunotherapy, and driven by low levels of the atypical protein kinase Cs (aPKCs) in the intestinal epithelium. We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA) which, along with reduced aPKC levels, predicts poor survival. HA promotes epithelial heterogeneity and the emergence of a tumor fetal metaplastic cell (TFMC) population endowed with invasive cancer features through a network of interactions with activated fibroblasts. TFMCs are sensitive to HA deposition, and their metaplastic markers have prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and liver metastasis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8+ T cells, including a proportion with resident memory features, and by blocking immunosuppression. [Display omitted] • Reduced aPKC drives HA deposition, the mCRC phenotype, and predicts poor survival • HA enhances malignancy and promotes CAF and epithelial heterogeneity in mCRC • Immunosuppression is maintained by cross-compartment interactions driven by HA • HA depletion blocks mCRC tumorigenesis and liver metastasis enabling immunotherapy Mesenchymal colorectal cancer (mCRC) is a highly desmoplastic and immune-excluded tumor with a poor prognosis. Martinez-Ordoñez et al. demonstrate that the synthesis of hyaluronan driven by a deficiency in the atypical protein kinase Cs in epithelial cells is a critical event in mCRC by promoting stroma crosstalks with invasive fetal metaplastic cells and immunosuppression. [ABSTRACT FROM AUTHOR]

Abstract: In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected ( R )-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and ( R )-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of ( R )-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described. [Copyright &y& Elsevier]

Abstract: We have previously reported that decreased intercellular adhesion molecule-1 (ICAM-1) expression in cancer cells is associated with liver metastasis of colorectal cancer. In this study, we have investigated the effect of ICAM-1 gene transfection into the human colorectal cancer cell line LM-H3 on cell adhesiveness and cytotoxicity of peripheral blood mononuclear cells (PBMC) to cancer cells. Furthermore, we have investigated the effects of this gene transfer on subcutaneous tumour and liver metastases of LM-H3 in nude mice. More PBMC adhered to ICAM-1 transfected LM-H3 cells, LM-H3/ICAM-1, than to non-transfected LM-H3 cells and control LM-H3/Vector. Lysis of LM-H3/ICAM-1 cells by PBMC was significantly increased compared with LM-H3/Vector. Liver metastases with LM-H3/ICAM-1 cells were fewer in number and smaller than metastases with LM-H3/Vector. Intra-tumoural injection of ICAM-1 adenoviral vector significantly inhibited the growth of subcutaneous LM-H3 tumour. In conclusion ICAM-1 gene transfection using adenovirus vector might be an effective therapy for liver metastasis of colorectal carcinoma. [Copyright &y& Elsevier]

Cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. We show that the upregulation of SOX2 is central to this process, which is repressed by protein kinase Cζ (PKCζ). PKCζ deficiency activates the reprogramming of colonic fibroblasts to generate a predominant SOX2-dependent CAF population expressing the WNT regulator Sfrp2 as its top biomarker. SOX2 directly binds the Sfrp1/2 promoters, and the inactivation of Sox2 or Sfrp1 / 2 in CAFs impaired the induction of migration and invasion of colon cancer cells, as well as their tumorigenicity in vivo. Importantly, recurrence-free and overall survival of colorectal cancer (CRC) patients negatively correlates with stromal PKCζ levels. Also, SOX2 expression in the stroma is associated with CRC T invasion and worse prognosis of recurrence-free survival. Therefore, the PKCζ-SOX2 axis emerges as a critical step in the control of CAF pro-tumorigenic potential. • PKCζ is lost in the stroma of poor-prognosis mesenchymal human CMS4 CRC • Stromal loss of PKCζ upregulates SOX2 to promote the CAF phenotype • Selective deletion of PKCζ in fibroblast activates the SOX2/SFRP1/2 axis in vivo • Stromal SOX2 negatively correlates with PKCζ and predicts poor survival in CRC Kasashima et al. describe a molecular mechanism whereby the loss of PKCζ in the stroma upregulates SOX2 to activate the reprogramming of colonic fibroblasts generating a SFRP1/2-expressing CAF population. This population supports epithelial tumor progression, revealing vulnerabilities in mesenchymal CMS4 colorectal cancer. [ABSTRACT FROM AUTHOR]