Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Thioredoxin domain-containing protein 9 protects cells against UV-B-provoked apoptosis via NF-κB/p65 activation in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma(cSCC),a type of non-melanoma skin cancer(NMSC),is the most common malignancy worldwide.Thioredoxin(TXN)domain-containing protein 9(TXNDC9)is a member of the TXN family that is important in cell differentiation.However,the biological function of this protein in cancer,particularly cSCC,is still unknown.In the present study,our experiments revealed the protective effects of TXNDC9 on UV-B-irritated cSCC cells.The initial findings showed that TXNDC9 is significantly upregulated in cSCC tissue and cells compared to normal skin tissue and keratinocytes.UV-B radiation robustly induces the expression of TXNDC9,and UV-B-induced cSCC cell death is boosted by TXNDC9 deficiency.Moreover,cSCC cells lacking TXNDC9 displayed attenuated activation of the NF-κB pathway.Additional studies by inhibiting TXNDC9 confirmed this finding,as TXNDC9 deficiency attenuated UV-B radiation-induced translocation of NF-κB p65 from the cytoplasm to the nucleus of cSCC.In conclusion,our work demonstrates the biological roles of TXNDC9 in cSCC progression and may provide a novel therapeutic target to treat cSCC in the future.

Giant cutaneous squamous cell carcinoma of the popliteal fossa skin:A case report

BACKGROUND Cutaneous squamous cell carcinoma(cSCC)is a common malignant hyperplasia of the skin epithelium.However,cSCC progressing to giant squamous cell carcinoma of the popliteal fossa skin has not been reported.We used full-thickness skin graft from the lower left quadrant of the abdomen to reconstruct the popliteal fossa skin defect in our patient.CASE SUMMARY A 64-year-old woman presented with a 3-year history of a progressively enlarged integumentary tumor located on her left popliteal fossa,which was surgically treated.The resultant defect(15 cm×25 cm)was repaired using full-thickness skin graft from the lower left quadrant of the abdomen.CONCLUSION Full-thickness skin graft is a good choice to repair popliteal fossa defect.

Recent progress in understanding the role of genes in the pathogenesis of cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma(cSCC)is the second most common skin tumor in humans.Ultraviolet(UV)radiation is an important environmental risk factor for cSCC;other risk factors include human papilloma virus(HPV)infection,chronic inflammation,and chronic wounds.A large proportion of patients present with an aggressive form of cSCC at the time of diagnosis,which is often accompanied by regional lymph node involvement and distant metastases.The long-term prognosis for these highly metastatic diseases is extremely poor,with a 10-year survival rate of less than 10%.Therefore,clarifying the pathogenesis of this tumor is of great significance and may contribute to the identification of novel biomarkers and development of new therapeutic strategies.In this review,we focus on the recent progress in genes related to the development of this tumor,intending to aid future investigations into the genetic alterations related to cSCC.

Risk prediction model for cutaneous squamous cell carcinoma in adult cardiac allograft recipients

BACKGROUND Heart transplant recipients are at higher risk of developing skin cancer than the general population due to the long-term immunosuppression treatment.Cancer has been reported as one of the major causes of morbidity and mortality for patients after heart transplantation.Among different types of skin cancers,cutaneous squamous cell carcinoma(cSCC)is the most common one,which requires timely screening and better management.AIM To identify risk factors and predict the incidence of cSCC for heart transplant recipients.METHODS We retrospectively analyzed adult heart transplant recipients between 2000 and 2015 extracted from the United Network for Organ Sharing registry.The whole dataset was randomly divided into a derivation set(80%)and a validation set(20%).Uni-and multivariate Cox regression were done to identify significant risk factors associated with the development of cSCC.Receiver operating characteristics curves were generated and area under the curve(AUC)was calculated to assess the accuracy of the prediction model.Based on the selected risk factors,a risk scoring system was developed to stratify patients into different risk groups.A cumulative cSCC-free survival curve was generated using the Kaplan-Meier method for each group,and the log-rank test was done to compare the intergroup cSCC rates.RESULTS There were 23736 heart-transplant recipients during the study period,and 1827 of them have been reported with cSCC.Significant predictors of post-transplant cSCC were older age,male sex,white race,recipient and donor human leukocyte antigen(HLA)mismatch level,malignancy at listing,diagnosis with restrictive myopathy or hypertrophic myopathy,heart re-transplant,and induction therapy with OKT3 or daclizumab.The multivariate model was used to predict the 5-,8-and 10-year incidence of cSCC and respectively provided AUC of 0.79,0.78 and 0.77 in the derivation set and 0.80,0.78 and 0.77 in the validation set.The risk scoring system assigned each patient with a risk score within the range of 0-11,based on which they were stratified into 4 different risk groups.The predicted and observed 5-year probability of developing cSCC match well among different risk groups.In addition,the log-rank test indicated significantly different cSCCfree survival across different groups.CONCLUSION A risk prediction model for cSCC among heart-transplant recipients has been generated for the first time.It offers a c-statistic of≥0.77 in both derivation and validation sets.

Treatment Recommendations among Radiation Oncologists in the Treatment of Cutaneous Squamous Cell Carcinoma with Perineural Invasion

Purpose: Post-operative radiotherapy (PORT) for resected cutaneous squamous cell carcinoma (CSCC) with perineural invasion (PNI) is controversial. Therefore, we conducted a survey to review treatment recommendations among Radiation Oncologists (ROs) in the management of CSCC with PNI. Materials & Methods: In March 2011, we contacted all ROs and trainees in the US through email addresses listed in the 2009 ASTRO directory. Our web-based survey presented clinical vignettes involving Mohs micrographically resected CSCC with microscopic PNI (mPNI) or clinical PNI (cPNI). For each vignette, ROs were asked to indicate if PORT was appropriate and to further specify the dose and volume to treat. Results: Three hundred fifty two responses were completed and analyzed. The majority of ROs (72%) had over 10 years of post residency experience. 64% of the sampled ROs had a special interest in treating head and neck cancers, and 64% treated 4 or more cases per year. Approximately 95% recommended PORT for cPNI whereas 59% recommended PORT for mPNI. Post residency experience (10+ yrs vs. <10 yrs) was associated with a greater propensity to recommend PORT for mPNI (48% vs. 30%, p = 0.005) and for mPNI of deep subcutaneous non-named nerve involvement (80% vs. 60%, p = 0.001). ROs treating 8 or more cases per year (vs. <7) were more likely to recommend PORT for mPNI in immunocompromised patients (74% vs. 57%, p = 0.01). Conclusions: Our study demonstrates significant variability among ROs in the management of CSCC with mPNI. For cases of cPNI, an overwhelming majority recommended PORT. In cases of mPNI, there was no consensus for recommending PORT, although experienced practitioners had a lower threshold for offering treatment. These results indicate the need for prospective clinical studies to clarify the role of PORT in CSCC patients with mPNI.

Inhibitory effect of survivin-shRNA on A431 cutaneous squamous cell carcinoma

Objective:To observe the effect of survivin-shRNA on A431 cutaneous squamous cell carcinoma(SCC)and explore the molecular biological mechanism of nuclear factorκB(NF-κB)in the inhibition of survivin-shRNA on cutaneous SCC.Methods:Survivin-shRNA adenovirus vector was constructed to screen out the best interference sequence.Nude mice were subcutaneously inoculated with the cultured A431 cell suspension to duplicate A431 transplanted tumor models.These mice were randomly divided into the blank control group,the rAd-EGFP negative control group,the rAd-survivin-shRNA transfection group and the Res positive control group,with 5 mice in each group.The corresponding reagents were injected into the tumors.All the mice were sacrificed on the 20th day.The tumor tissues were isolated,with tumor volume and tumor weight measured,the tumor growth curves were accordingly plotted and the tumor inhibition rate was consequently calculated.Hematoxylin-eosin(HE)staining was used to observe the cellular morphology of the tumors.TUNEL was applied to the detection of cell apoptosis.Western blot was applied to the detection of the expression of Survivin,inhibitor of NF-κB(IκB),P65,P53 and Caspase-3.Results:As to the transplanted tumors,tumor volume and tumor weight were decreased in nude mice in the rAd-survivinshRNA transfection group and the Res positive control group,in comparison with the blank control group and the rAd-EGFP negative control group,the differences were of statistical significance(p<.05);The results of TUNEL showed that the apoptosis rates were significantly increased in the rAd-survivin-shRNA transfection group and the Res positive control group,in comparison with the blank control group and the rAd-EGFP negative control group,the difference was statistically significant(p<.05);In the rAd-survivin-shRNA transfection group and the Res positive control group,the microscopic observation showed a small amount of sparsely-distributed tumor cells,degenerative liquefactive necrosis,cancer cell shrinkage and round-shape,and karyopycnosis;The expressions of Survivin and P65 proteins were decreased in the rAd-survivin-shRNA transfection group and the Res positive control group,in comparison with the blank control group and the rAd-EGFP negative control group,the differences were statistically significant(p<.05),while the expressions of IκB,P53 and Caspase-3 proteins were significantly increased,in comparison with the blank control group and the rAd-EGFP negative control group,the differences were statistically significant(p<.05).Conclusions:Survivin-shRNA can inhibit the growth of the transplanted tumors in cutaneous SCC nude mice,one of the mechanisms is to promote the apoptosis of tumor cells and inhibit the growth of SCC transplanted tumors by inhibiting the NF-κB signaling pathway and then activating the tumor suppressor gene P53.

Cyclophosphamide,fluorouracil and low-dose interleukin-2 and salvage combination chemotherapy in advanced cutaneous squamous cell carcinoma

A 70-year-old female with metastatic cutaneous squamous cell carcinoma(cSCC)and low-grade non-Hodgkin’s lymphoma,not amenable to cisplatin combination therapy,was treated with cyclophoshamide(Cyc)-fluorouracil(FU)-interleukin-2(IL-2)in light of high tumor immunogenicity and the potential activity of this regimen.Cyc 300 mg/m^(2)and FU 500 mg/m^(2)intravenously on day 1 and IL-24.5 MIU/day on days 3-6 and 17-20 subcutaneously every 4 weeks;Carboplatin(C)AUC 2 and paclitaxel(P)85 mg/m^(2)on days 1,8 and 15±capecitabine(Cape)every 4 weeks.After partial remission(PR)of lung metastases and local control with two cycles of first therapy followed by PR with five cycles of CP±Cape,right mastectomy was performed with evidence of viable tumor.Subsequently,the patient underwent 3 cycles of chlorambucil and is alive after 13 months of follow-up.Safety and activity of chemo-immunotherapy and salvage treatment can be achieved in cSCC.

MAPK/ERK regulation of P53 in human epidermoid carcinoma cell line A431

Objective:To observe the impact of activation and inhibition of mitogen activated protein kinases(MAPK)/extracellular signalregulated protein kinase(ERK)signaling pathway on the proliferation and apoptosis of cutaneous squamous cell carcinoma(SCC).cells and investigate the interaction mechanism between MAPK/ERK signaling pathway and tumor suppressor gene P53 in SCC.Methods:Human A431 cells were cultured and divided into MAPK/ERK inhibition groups with low-,medium-and highconcentration of inhibitors(PD98059+DMSO),MAPK/ERK activation groups with low-,medium-and high-concentration of stimuli(IGF+PBS)and blank control group(DMSO).The cell proliferation in vitro was detected by MTT assay,with the cell apoptosis detected by flow cytometry(FCM)and the protein expression of P-ERK and P53 detected by western blot in each group.Results:The A431 cell proliferation was inhibited by different concentrations of PD98059 with a clear concentration-effect and time-effect relationship(p<.05);and the cell proliferation was promoted by the different concentrations of IGF with a clear concentration-effect and time-effect relationship(p<.05).The FCM results showed a significant increase in the apoptosis rate of A431 cells which were treated with PD98059,with a clear concentration-effect relationship(p<.05);while the apoptosis rate was decreased significantly after A431 cells were treated with IGF,also with a concentration-effect relationship(p<.05).The western blot results showed that the expression of P-ERK protein was decreased but the expression of P53 was increased after A431 cells were treated with PD98059.With the concentration of PD98059 going up,the decrease in P-ERK and the increase in P53 were more significant(p<.05);while the expression of P-ERK protein was increased but the expression of P53 was decreased after A431 cells were treated with IGF.With the concentration of IGF going up,the increase in P-ERK and the decrease in P53 were more significant(p<.05).According to Pearson correlation analysis,the expression of P53 was negatively correlated to that of P-ERK(p<.05).Conclusions:After MAPK/ERK signaling pathway was activated by IGF in A431 cells,the expression of pro-apoptotic factor P53 was decreased with the ability of cell proliferation enhanced and the ability of apoptosis reduced.However,after the inhibition of MAPK/ERK signaling pathway,the expression of pro-apoptotic factor P53 was increased with the ability of cell proliferation reduced and the ability of apoptosis increased.

The crucial roles of m^(6)A RNA modifications in cutaneous cancers:Implications in pathogenesis,metastasis,drug resistance,and targeted therapies

N6-methyladenosine(m^(6)A)is the most abundant internal modification on RNA.It is a dynamical and reversible process,which is regulated by m^(6)A methyltransferase and m^(6)A demethylase.The m^(6)A modified RNA can be specifically recognized by the m^(6)A reader,leading to RNA splicing,maturation,degradation or translation.The abnormality of m^(6)A RNA modification is closely related to a variety of biological processes,especially the occurrence and development of tumors.Recent studies have shown that m^(6)A RNA modification is involved in the pathogenesis of skin cancers.However,the precise molecular mechanisms of m^(6)A-mediated cutaneous tumorigenesis have not been fully elucidated.Therefore,this review will summarize the biological characteristics of m^(6)A modification,its regulatory role and mechanism in skin cancers,and the recent research progress of m^(6)A-related molecular drugs,aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.