Targetin Semaphorin 4D in Cancer: A Look from Different Perspectives

Semaphorin 4D (Sema4D) plays a role in various cell types including B lymphocytes, differentiating neurons, endothelial cells, and cancer cells. Preclinical and in vitro studies have shown that Sema4D-directed antibodies in combination with immune checkpoint inhibitors reshape the tumor microenvironment by promoting recruitment of effector lymphocytes and antigen-presenting cells, while reducing immunosuppressive cell types, which ultimately leads to tumor rejection. Hence, early-stage clinical trials with combination therapies including anti-Sema4D antibodies are ongoing. In this issue of Cancer Research, Zuazo-Gaztelu and colleagues report an unexpected proinvasive effect induced by anti-Sema4D antibodies in a preclinical model of neuroendocrine pancreatic cancer (Rip1-Tag2), mediated by retrograde signaling of transmembrane Sema4D in macrophages, which increases their recruitment to tumors, SDF-1 secretion, and metastasis-promoting phenotype

Validation of Esaso Classification of Diabetic Maculopathy

Purpose: To test reliability and reproducibility of ESASO morphologic OCT-based classification of diabetic maculopathy (DM). Methods: This is a multi-center cross-sectional study including a coordination center (CC) and 18 participating centers (PCs). After instruction on the correct use of ESASO Classification, the validation process was carried out in two consecutive stages. In the first retrospective phase, we evaluated the concordance between PCs and CC in the staging of OCT images collected during PCs' daily activity (608 images). In a second prospective phase, we analyzed the inter-observer agreement of staging assigned by each PCs to OCT images selected by the CC (22 images). Results: The overall concordance achieved in the retrospective phase was 89.8% (Kappa = 0.83 (95% CI: 0.78-0.87); p<0.0001). In 99.5% of cases, concordance did not differ by more than one stage. In the prospective phase, PCs reached an inter-operator agreement of 93.0% (Krippendorff's Alpha = 0.953, 95% CI: 0.929-0.977, p<0.0001). Any discrepancy among the 22 images was within one stage. Conclusion: The results achieved in this study confirm that ESASO OCT-based Classification can be considered as an easy and reproducible method to stage DM during clinical practice. A diffused use of a common and validated method to describe the progression of retinal damage in DM may offer several clinical and scientific advantages

Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential

Semaphorin 4C (Sema4C) expression in human breast cancers correlates with poor disease outcome. Surprisingly, upon knock-down of Sema4C or its receptor PlexinB2 in diverse mammary carcinoma cells (but not their normal counterparts), we observed dramatic growth inhibition associated with impairment of G2/M phase transition, cytokinesis defects and the onset of cell senescence. Mechanistically, we demonstrated a Sema4C/PlexinB2/LARG-dependent signaling cascade that is required to maintain critical RhoA-GTP levels in cancer cells. Interestingly, we also found that Sema4C upregulation in luminal-type breast cancer cells drives a dramatic phenotypic change, with disassembly of polarity complexes, mitotic spindle misorientation, cell\u2013cell dissociation and increased migration and invasiveness. We found that this signaling cascade is dependent on the PlexinB2 effectors ErbB2 and RhoA-dependent kinases. Moreover, Sema4C-overexpressing luminal breast cancer cells upregulated the transcription factors Snail, Slug and SOX-2, and formed estrogen-independent metastatic tumors in mice. In sum, our data indicate that Sema4C/PlexinB2 signaling is essential for the growth of breast carcinoma cells, featuring a novel potential therapeutic target. In addition, elevated Sema4C expression enables indolent luminal-type tumors to become resistant to estrogen deprivation, invasive and metastatic in vivo, which could account for its association with a subset of human breast cancers with poor prognosis

Mutated axon guidance gene PLXNB2 sustains growth and invasiveness of stem cells isolated from cancers of unknown primary

The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole-exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by comparing the mutational landscape of CUPs with that of most other human tumor types, it emerged a consistent enrichment of changes in genes belonging to the axon guidance KEGG pathway. In particular, G842C mutation of PlexinB2 (PlxnB2) was predicted to be activating. Indeed, knocking down the mutated, but not the wild-type, PlxnB2 in CUP stem cells resulted in the impairment of self-renewal and proliferation in culture, as well as tumorigenic capacity in mice. Conversely, the genetic transfer of G842C-PlxnB2 was sufficient to promote CUP stem cell proliferation and tumorigenesis in mice. Notably, G842C-PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation, and EGFR blockade impaired the viability of CUP cells reliant on the mutated receptor. Moreover, the mutated PlxnB2 elicited CUP cell invasiveness, blocked by EGFR inhibitor treatment. In sum, we found that a novel activating mutation of the axon guidance gene PLXNB2 sustains proliferative autonomy and confers invasive properties to stem cells isolated from cancers of unknown primary, in EGFR-dependent manner

Early DMO: a predictor of poor outcomes following cataract surgery in diabetic patients. The DICAT-II study

Background: The prospective DIabetes and CATaract Study II (DICAT II) was performed to characterise the risks of cataract surgery to the retinae of patients with early diabetic macular oedema (E-DMO). Methods: DICAT II was a prospective, comparative, multicentre, observational study involving six Italian clinics. Patients were aged 6555 years, had type 1 or 2 diabetes with spectral-domain optical coherence tomography evidence of ESASO classification Early DMO. Group 1 eyes (78 eyes, 78 patients) underwent phacoemulsification-based cataract surgery. Group 2 eyes (65 eyes, 65 patients) had E-DMO and either clear media or had undergone uncomplicated cataract surgery 651 year previously. Central subfield thickness (CST) and best-corrected visual acuity (BCVA) were assessed in both groups. Results: The negative impact of surgery on CST was evident after the first postoperative week; CST peaked during the first month, then rapidly decreased. CST worsening 6510 \ub5m was observed in 63/78 eyes (80.7%) and 29/65 eyes (44.6%) in Groups 1 and 2, respectively (p < 0.0001). CST worsening of 6550 \ub5m was observed in 51 eyes (65.4%) and 10 eyes (15.4%) in Groups 1 and 2, respectively (p < 0.0001). Mean CST worsening was lower in Group 2 than in Group 1 (38.6 \ub1 30.4 \ub5m vs 85.5 \ub1 55.3 \ub5m, p < 0.0001) with a lower BCVA loss (-2.6 \ub1 3.5 letters vs -8.2 \ub1 6.2 letters, p < 0.0001). Higher glycaemic levels and HBA1c levels were significantly associated with the risk of >50 \u3bcm CST worsening in eyes from both groups. Conclusion: Early DMO is associated with poorer outcomes after cataract surgery and requires close pre- and postoperative monitoring