Partial or even complete cancer regression can be achieved in some patients with current cancer treatments. However, such initial responses are almost always followed by relapse, with the recurrent cancer being resistant to further treatments. The discovery of therapeutic approaches that counteract relapse is, therefore, essential for advancing cancer medicine. Cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential, drug sensitivity, and their potential to metastasize and cause relapse. Indeed, hypermalignant cancer cells, termed cancer stem cells or stemness-high cancer cells, that are highly tumorigenic and metastatic have been isolated from cancer patients with a variety of tumor types. Moreover, such stemness-high cancer cells are resistant to conventional chemotherapy and radiation. Here we show that BBI608, a small molecule identified by its ability to inhibit gene transcription driven by Stat3 and cancer stemness properties, can inhibit stemness gene expression and block spherogenesis of or kill stemnesshigh cancer cells isolated from a variety of cancer types. Moreover, cancer relapse and metastasis were effectively blocked by BBI608 in mice. These data demonstrate targeting cancer stemness as a novel approach to develop the next generation of cancer therapeutics to suppress cancer relapse and metastasis.cancer stemness | relapse | BBI608 C urrent cancer treatments ultimately fail owing to metastasis and relapse. Although chemotherapy can induce partial or even complete cancer regression in some patients, such initial responses are invariably followed by relapse, with the recurrent cancer being highly resistant to further chemotherapy, resulting in very limited survival benefits (1-3). Modern therapeutics designed to specifically target activating mutations are quite effective in inducing cancer regression in patients driven by such activating mutations; however, these treatments are also invariably followed by relapse with tumors that no longer respond to the targeted agent (2, 3). The discovery of novel therapeutic approaches that counteract cancer relapse is, therefore, urgently required for advancing cancer treatment.The idea that cancer is composed of a group of near-homogenous, ectopically growing cells has been replaced with a more complex model in which cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential to metastasize and cause relapse. The increased understanding of the genomic and proteomic complexity of tumor heterogeneity further highlights the extreme heterogeneity of cancer cells (4).Subpopulations of cancer cells with extremely high tumorigenic potential, termed cancer stem cells or stem-like cancer cells, have been isolated from cancer patients with a variety of tumor types (5-13) and found to have high stemness properties (5-15). Stemness, initially defined by the expression of stem cells genes, is a property shared by embryonic stem cells and adult stem cells (16). In ...

Aim To describe a group of distinct low‐grade oncocytic renal tumours that demonstrate CD117 negative/cytokeratin (CK) 7‐positive immunoprofile. Methods and results We identified 28 such tumours from four large renal tumour archives. We performed immunohistochemistry for: CK7, CD117, PAX8, CD10, AMACR, e‐cadherin, CK20, CA9, AE1/AE3, vimentin, BerEP4, MOC31, CK5/6, p63, HMB45, melan A, CD15 and FH. In 14 cases we performed array CGH, with a successful result in nine cases. Median patient age was 66 years (range 49–78 years) with a male‐to‐female ratio of 1:1.8. Median tumour size was 3 cm (range 1.1–13.5 cm). All were single tumours, solid and tan‐brown, without a syndromic association. On microscopy, all cases showed solid and compact nested growth. There were frequent areas of oedematous stroma with loosely arranged cells. The tumour cells had oncocytic cytoplasm with uniformly round to oval nuclei, but without significant irregularities, and showed only focal perinuclear halos. Negative CD117 and positive CK7 reactivity were present in all cases (in two cases there was focal and very weak CD117 reactivity). Uniform reactivity was found for PAX8, AE1/AE3, e‐cadherin, BerEP4 and MOC31. Negative stains included CA9, CK20, vimentin, CK5/6, p63, HMB45, Melan A and CD15. CD10 and AMACR were either negative or focally positive; FH was retained. On array CGH, there were frequent deletions at 19p13.3 (seven of nine), 1p36.33 (five of nine) and 19q13.11 (four of nine); disomic status was found in two of nine cases. On follow‐up (mean 31.8 months, range 1–118), all patients were alive with no disease progression. Conclusion Low‐grade oncocytic tumours that are CD117‐negative/CK7‐positive demonstrate consistent and readily recognisable morphology, immunoprofile and indolent behaviour.

Aberrant vascular network is a hallmark of cancer. However, the role of vascular endothelial cells (VECs)-expressing PD-L1 in tumor immune microenvironment and antiangiogenic therapy remains unclear. In this study, we used the specimens of cancer patients for immunohistochemical staining to observe the number of PD-L1 + CD34 + VECs and infiltrated immune cells inside tumor specimens. Immunofluorescence staining and flow cytometry were performed to observe the infiltration of CD8 + T cells and FoxP3 + T cells in tumor tissues. Here, we found that PD-L1 expression on VECs determined CD8 + T cells', FoxP3 + T cells' infiltration, and the prognosis of patients with lung adenocarcinoma. Anlotinib downregulated PD-L1 expression on VECs through the inactivation of AKT pathway, thereby improving the ratio of CD8/FoxP3 inside tumor and remolding the immune microenvironment. In conclusion, our results demonstrate that PD-L1 high expression on VECs inhibits the infiltration of CD8 + T cells, whereas promotes the aggregation of FoxP3 + T cells into tumor tissues, thus becoming an "immunosuppressive barrier". Anlotinib can ameliorate the immuno-microenvironment by downregulating PD-L1 expression on VECs to inhibit tumor growth.

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Renal cell carcinoma with (angio) leiomyomatous stroma (RCCLMS) is included as a provisional entity in the 2016 World Health Organization (WHO) classification of renal epithelial neoplasia; however, debate remains whether it represents a distinct entity or a heterogenous group of renal cell carcinomas (RCCs) with overlapping morphology. Also, its relationship to similar tumors occurring in the setting of tuberous sclerosis complex (TSC) is not fully addressed. We analyzed the clinicopathologic, immunohistochemical, and molecular characteristics of 23 sporadic RCCs associated with smooth muscle stroma and classified them into 2 groups, independent of molecular results: (1) RCCLMS (n=18) and (2) clear cell renal cell carcinoma (CCRCC) (n=5). The classification of a case as “RCCLMS” was based on morphologic comparison with 5 “index” RCCs from 3 patients with TSC showing similar features and the presence of diffuse CK7 expression. To investigate mutational and copy number alterations, a 170-gene solid tumor panel was utilized to sequence 14 RCCLMSs and control of 5 CCRCCs. Also, 4 RCCLMSs, suspicious for chromosome 8 monosomy, were further evaluated by a broader 479 gene sequencing panel that included ELOC (also referred to as TCEB1). Clinical information and follow-up data were obtained from electronic medical records. The mean age of patients with RCCLMS was 52 years (range, 33 to 69) with male:female ratio of 1:2. Macroscopically, all tumors were solitary and predominantly (82%) tan/red, circumscribed, and solid. The average tumor size was 2.3 cm (range, 1.1 to 4.5). Microscopically, the distinctive feature included tumor nodules of elongated and frequently branching tubules lined by cells with voluminous clear to mildly eosinophilic cytoplasm (100%), separated by focal to prominent smooth muscle stroma. Additional frequently identified features included: biphasic pattern of collapsed acini surrounding tubules with voluminous cytoplasm (50%), focal papillary architecture (39%), peritumoral lymphoid aggregates (39%), and hemosiderin-laden macrophages (33%). All 11 (100%) RCCLMSs with available staging information were pT1; 78% were WHO/International Society of Urologic Pathology (ISUP) grade 2 and 22% grade 3. Immunophenotypically, RCCLMSs were characterized by diffuse CK7, CAM5.2 and CD10 reactivity (100%). All patients with available follow-up (n=10) were alive and without disease progression after a mean and median follow-up of 25.2 (range: 1 to 58) and 25 months, respectively. The molecular results showed recurrent mutations in all RCCLMS: TSC1 (4), TSC2 (4), MTOR (6), and/or ELOC (2). Five control CCRCCs demonstrated primary alterations in VHL gene, while all 14 RCCLMS cases tested had intact VHL gene. Of 2 RCCLMSs with confirmed monosomy 8, 1 showed a hotspot ELOC mutation without TSC/MTOR mutations, and 1 showed a previously undescribed 3-bp in-frame ELOC deletion, along with a truncating TSC1 mutation. In conclusion, RCCLMS, as defined herein, harbors recurrent mutations of TSC1/TSC2, MTOR, and/or ELOC, consistent with hyperactive MTOR complex. Our findings argue that these tumors represent the sporadic counterpart to morphologically identical tumors occurring in TSC patients. Finally, the data support that RCCLMS is a novel subtype of RCC with unique morphologic, immunohistochemical, and molecular characteristics that is distinct from CCRCC and clear cell-papillary RCC.

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Ferroptosis is a form of iron-dependent programmed cell death. Regulate ferroptosis in tumor cells is a novel treatment modality. The present study aimed to investigate ferroptosis-related long non-coding RNAs (lncRNAs) and construct a prognostic model for colon adenocarcinoma (COAD). RNA- sequencing data and ferroptosis-related genes were obtained from The Cancer Genome Atlas database and FerrDb database. COAD patients were randomly assigned to training- and validation groups. The Least Absolute Shrinkage and Selection Operator regression and Cox regression model were used to determine and develop a predictive model. The model was corroborated using the validation group and the entire group. In total, 259 ferroptosis-related genes and 905 ferroptosis-related LncRNAs were obtained. Cox model revealed and constructed seven ferroptosis-related LncRNAs signature (LINC01503, AC004687.1, AC010973.2, AP001189.3, ARRDC1-AS1, OIP5-AS1, and NCK1-DT). Patients were assigned into two groups according to the median risk score. Kaplan–Meier survival curves showed that overall survival between high- and low-risk groups was statistically significant (P<0.01). Cox multivariate analysis seven ferroptosis-related LncRNAs signature was an independent risk factor for COAD outcomes (P<0.05). The relationship between seven ferroptosis-related LncRNAs and clinicopathological features was also examined. The principal component analysis showed a difference between high- and low-risk groups intuitively. With the aid of gene set enrichment analysis, the underlying mechanisms of seven ferroptosis-related LncRNAs were uncovered, including the MAPK signaling pathway, mTOR signaling pathway, and glutathione metabolism pathway. Finally, we established and validated seven ferroptosis-related lncRNAs signature for COAD patients to predict survival. These results may provide meaningful targets for future study.

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