Junctional Adhesion Molecule-C Mediates the Recruitment of Embryonic-Endothelial Progenitor Cells to the Perivascular Niche during Tumor Angiogenesis

The homing of Endothelial Progenitor Cells (EPCs) to tumor angiogenic sites has been described as a multistep process, involving adhesion, migration, incorporation and sprouting, for which the underlying molecular and cellular mechanisms are yet to be fully defined. Here, we studied the expression of Junctional Adhesion Molecule-C (JAM-C) by EPCs and its role in EPC homing to tumor angiogenic vessels. For this, we used mouse embryonic-Endothelial Progenitor Cells (e-EPCs), intravital multi-fluorescence microscopy techniques and the dorsal skin-fold chamber model. JAM-C was found to be expressed by e-EPCs and endothelial cells. Blocking JAM-C did not affect adhesion of e-EPCs to endothelial monolayers in vitro but, interestingly, it did reduce their adhesion to tumor endothelium in vivo. The most striking effect of JAM-C blocking was on tube formation on matrigel in vitro and the incorporation and sprouting of e-EPCs to tumor endothelium in vivo. Our results demonstrate that JAM-C mediates e-EPC recruitment to tumor angiogenic sites, i.e., coordinated homing of EPCs to the perivascular niche, where they cluster and interact with tumor blood vessels. This suggests that JAM-C plays a critical role in the process of vascular assembly and may represent a potential therapeutic target to control tumor angiogenesis

The evolution of autologous breast reconstruction.

With breast cancer (BC) becoming more treatable, breast reconstruction has become an integral part of BC treatment. Nowadays, implant-based breast reconstruction is more common. However, there is a growing interest in autologous breast reconstruction due to the increasing awareness of implant-related complications. This work provides a comprehensive overview of the evolution of autologous reconstruction techniques of the breast and the nipple-areolar complex (NAC)

Autologous fat grafting efficacy in treating PostMastectomy pain syndrome: A prospective multicenter trial of two Senonetwork Italia breast centers.

Postmastectomy pain syndrome (PMPS) represents a common complication following breast surgery defined as a chronic neuropathic pain located in the front of the chest, in the axilla and in the upper arm that for more than 3 months after surgery. Several medications prove to be ineffective while autologous fat grafting revealed to be an innovative solution in the treatment of neuropathic pain syndromes based on retrospective studies. For this reason, we performed a prospective multicenter trial to reduce the memory bias and further increase the evidence of the results. From February 2018 to March 2019, 37 female patients aged between 18 and 80 years, underwent mastectomy or quadrantectomy with pathologic scarring and chronic persistent neuropathic pain, compatible with PMPS, are been included in the study and treated with autologous fat grafting. During the enrollment phase, patients were asked to estimate pain using the Visual Analogue Scale (VAS) and POSAS questionnaire in order to evaluate scar outcomes. The VAS scale, starting from 6.9 (1.3), decreased in the first month by 3.10 (1.59), continuing to fall by 0.83 (1.60) to 3 months and by 0.39 (2.09) at 6 months. Statistical analysis showed a significant reduction after 1 month (P < .0001) and 3 months (P < .005). All POSAS grades documented a statistically significant reduction (P < .0001) of the scores by both observers and patients. We observed that no significant association was found between age, BMI, menopausal status of patients, days from oncologic surgery to autologous fat grafting and reduction of VAS values over time while both smoking and axillary dissection were observed as the main factor significantly associated with a reduced clinical efficacy (respectively, P = .0227 and P = .0066). Our prospective multicenter trial confirms the efficacy of fat grafting in the treatment of PMPS based on the principle of regenerative medicine with a satisfactory response in terms of pain reduction and improvement of the quality of the treated tissues. Clinical questionnaires show that the cicatricial areas improve in terms of color, thickness, skin pliability, and surface irregularities. Regenerative effect is based also on the adoption of needles. The combined effect of fat grafting and needles determines a clinical full response

Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation

There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available threedimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed. To address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high-throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)- mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)g inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two-dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease.: We have established and validated a suite of highly reproducible tumor microplate threedimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds.This work was funded by The National Centre for the Replacement, Refinement and Reduction of Animals in Research (G1000121 ID no. 94513), Cancer Research UK (grant number C309/A8274), and by Red Tematica de Investigación Cooperativa en Cancer (RD06/0020/1022). We acknowledge NHS funding to the NIHR Biomedical Research Centre. MM is supported by a postdoctoral research contract (FIS, Program ‘Sara Borrell’, Instituto de Salud Carlos III), Ministerio de Ciencia e Innovación, Spain

Immediate direct-to-implant breast reconstruction: A single center comparison between different procedures

BackgroundThe increased incidence of conservative mastectomy operations (nipple- and skin- sparing) has increased the frequency of immediate breast reconstructions (IBR). In order to guarantee patients the best possible aesthetic outcome, the least chance of complications and moreover, the least postoperative pain, the technique with prepectoral prosthetic pocket was recently reconsidered with the use of ADM. This is the first study using Fortiva® in prepectoral breast reconstruction, and it compares the outcomes of three different patient populations (undergoing retromuscular, prepectoral and prepectoral reconstruction with ADM). The authors suggest that prepectoral breast reconstruction with ADM may bring benefits compared to the current standard technique (retromuscular) as well as compared to the prepectoral reconstruction without ADM.MethodsRetrospective data analysis of patients who underwent mastectomy followed by immediate breast reconstruction with silicone implants (DTI), performed by a team of breast surgeons and plastic surgeons. Logistic factor regressions were performed in order to investigate the effects of the three different intervention techniques on the incidence of complications. Fisher's exact test was used to analyze the differences in the occurrence of each complication. Mann Whitney test was used to compare the averages of referred pain. A p value &lt;0.05 was considered significant.ResultsA total of 67 patients underwent DTI reconstruction, of which 43 with retromuscular prosthesis, 13 prepectoral and 11 prepectoral with ADM. We found a significantly lower incidence of surgical complications with ADM, exclusively in comparison with retromuscular reconstruction (p = 0.028). It emerges prepectoral reconstruction with ADM involves significantly less visibility of the implant than both the prepectoral surgery without ADM (p = 0.013) and the retromuscular technique (p = 0.029). Finally, postoperative pain referred at twelfth month is significantly less relevant in the group with prepectoral prosthesis and ADM, both in the group with retromuscular (p &lt; 0.001) and prepectoral without ADM (p = 0.001).ConclusionsThis study demonstrates that immediate prepectoral breast reconstruction with ADM is a safe and reliable technique, able to exceed some type of limits imposed by prepectoral reconstruction. Moreover, it provides benefits if compared to the current standard technique. In the future, this technique could also be added to it, after a proper selection of patients in pre- and intraoperative time

The evolution of breast prostheses.

Every year approximately 1.5 million prostheses are implanted worldwide for breast augmentation and reconstructive indications. The modern breast implant as we know was released to the open market in 1963. It has gone through intense phases of development which have improved the initially primitive and limited devices to current-day devices, which exhibit a tremendous range of surface textures, sizes, gel consistencies, and anatomical shapes. This article explores the evolution of breast implants providing historical facts and technical details

Manipulating the tumor immune microenvironment to improve cancer immunotherapy: IGF1R, a promising target

Cancer immunotherapy has made impressive advances in improving the outcome of patients affected by malignant diseases. Nonetheless, some limitations still need to be tackled to more efficiently and safely treat patients, in particular for those affected by solid tumors. One of the limitations is related to the immunosuppressive tumor microenvironment (TME), which impairs anti-tumor immunity. Efforts to identify targets able to turn the TME into a milieu more auspicious to current immuno-oncotherapy is a real challenge due to the high redundancy of the mechanisms involved. However, the insulin-like growth factor 1 receptor (IGF1R), an attractive drug target for cancer therapy, is emerging as an important immunomodulator and regulator of key immune cell functions. Here, after briefly summarizing the IGF1R signaling pathway in cancer, we review its role in regulating immune cells function and activity, and discuss IGF1R as a promising target to improve anti-cancer immunotherapy