Shi-pi-xiao-ji formula suppresses hepatocellular carcinoma by reducing cellular stiffness through upregulation of acetyl-coA acetyltransferase 1

BACKGROUND Previous studies have shown that the Shi-pi-xiao-ji(SPXJ)herbal decoction formula is effective in suppressing hepatocellular carcinoma(HCC),but the underlying mechanisms are not known.Therefore,this study investigated whether the antitumor effects of the SPXJ formula in treating HCC were mediated by acetyl-coA acetyltransferase 1(ACAT1)-regulated cellular stiffness.Through a series of experiments,we concluded that SPXJ inhibits the progression of HCC by upregulating the expression level of ACAT1,lowering the level of cholesterol in the cell membrane,and altering the cellular stiffness,which provides a new idea for the research of traditional Chinese medicine against HCC.AIM To investigate the anti-tumor effects of the SPXJ formula on the malignant progression of HCC.METHODS HCC cells were cultured in vitro with SPXJ-containing serum prepared by injecting SPXJ formula into wild-type mice.The apoptotic rate and proliferative,invasive,and migratory abilities of control and SPXJ-treated HCC cells were compared.Atomic force microscopy was used to determine the cell surface morphology and the Young’s modulus values of the control and SPXJ-treated HCC cells.Plasma membrane cholesterol levels in HCC cells were detected using the Amplex Red cholesterol detection kit.ACAT1 protein levels were estimated using western blotting.RESULTS Compared with the vehicle group,SPXJ serum considerably reduced proliferation of HCC cells,increased stiffness and apoptosis of HCC cells,inhibited migration and invasion of HCC cells,decreased plasma membrane cholesterol levels,and upregulated ACAT1 protein levels.However,treatment of HCC cells with the water-soluble cholesterol promoted proliferation,migration,and invasion of HCC cells as well as decreased cell stiffness and plasma membrane cholesterol levels,but did not alter the apoptotic rate and ACAT1 protein expression levels compared with the vehicle control.CONCLUSION SPXJ formula inhibited proliferation,invasion,and migration of HCC cells by decreasing plasma membrane cholesterol levels and altering cellular stiffness through upregulation of ACAT1 protein expression.

THE EXPRESSION OF CYTOKERATINS IN HUMAN HEPATOCELLULAR AND CHOLANGIOCELLULAR CARCINOMAS

In order to determine the usefulness value of the antibodies to cytokeratins(CK) of'bile duct type'in the differential diagnosis between hepatocellular carcinoma(HCC) and cholangiocellular carcinoma(CC),we have made an immunocytochemical investigation,using the antibodies specifically recognizing CK19 and CK18,seperately,in liver,and laminin(LN) antibody.All the CC examined(10 cases) were found CK19-positive;interestingly,CK19-positive cancer cells were also observed in 38% of HCCs(14/37).Therefore,CK19 was not a reliable marker in differentiating HCC from CC,in our consideration.The CK19 expression in HCC was showed to be irrelevant to their differentiation degres,but related to the histologic subtypes which indicated the directions of their differentiation.CK19 expression was observed in all the HCC cell nests with glandular differentiation,and an untontinuous LN-Positive basement membrane-like structure was immunolocalized around these cells.Which indicated that the glandular differentiation and CK19 expression in HCC were also related to the LN deposition,as in fetal liver and some chronic liver disorders.

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms,some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC.

Short-term interval combined chemoembolization and radiofrequency ablation for hepatocellular carcinoma

AIM: To investigate hepatic function after combined transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) with a short-term interval (0-2 d).

Recent advances in immunotherapy for hepatocellular carcinoma

Background:Treatment of hepatocellular carcinoma(HCC)is challenging as most patients are diagnosed at advanced stage with underlying chronic liver conditions.Conventional systemic chemotherapy has failed in HCC,and the clinical efficacy of FDA-approved molecular targeted agents such as sorafenib and lenvatinib remains unsatisfactory.Data sources:Literature search was conducted in Pub Med for relevant articles published before January 2021.The search aimed to identify recent developments in immune-based treatment approaches for HCC.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Two immune checkpoint inhibitors(ICIs),nivolumab and pembrolizumab were approved as monotherapies,which has revolutionized HCC treatment.Besides,combination ICIs have also got accelerated FDA approval recently.Immune-based therapies have challenged targeted drugs owing to their safety,tolerability,and survival benefits.In addition to the significant success in ICIs,other immunotherapeutic strategies such as cancer vaccine,chimeric antigen receptor T-cells,natural killer cells,cytokines,and combination therapy,have also shown promising outcomes in clinical trials.Various diagnostic and prognostic biomarkers have been identified which can help in clinical decision making when starting treatment with ICIs.Conclusions:Immunotherapy has emerged as one of the mainstream treatment modalities for advanced HCC in recent years.However,challenges such as low response rate and acquired resistance in previously respondent patients still exist.Further research is needed to understand the unique resistance mechanism to immunotherapy and to discover more predictive biomarkers to guide clinical decision making.

Roles of Tregs in development of hepatocellular carcinoma:A meta-analysis

AIM: To assess systematically the association between regulatory T cells (Tregs) and hepatocellular carcinoma (HCC).

WJH 6^(th) Anniversary Special Issues(2): Hepatocellular carcinoma Mammalian target of rapamycin inhibition in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.

Murine hepatocellular carcinoma derived stem cells reveal epithelial-to-mesenchymal plasticity

AIM To establish a model to enrich and characterize stemlike cells from murine normal liver and hepatocellular carcinoma(HCC) cell lines and to further investigate stem-like cell association with epithelial-to-mesenchymal transition(EMT).METHODS In this study,we utilized a stem cell conditioned serumfree medium to enrich stem-like cells from mouse HCC and normal liver cell lines,Hepa 1-6 and AML12,respectively.We isolated the 3-dimensional spheres and assessed their stemness characteristics by evaluating theRNA levels of stemness genes and a cell surface stem cell marker by quantitative reverse transcriptase-PCR(q RTPCR).Next,we examined the relationship between stem cells and EMT using q RT-PCR.RESULTS Three-dimensional spheres were enriched by culturing murine HCC and normal hepatocyte cell lines in stem cell conditioned serum-free medium supplemented with epidermal growth factor,basic fibroblast growth factor and heparin sulfate.The 3-dimensional spheres had enhanced stemness markers such as Klf4 and Bmi1 and hepatic cancer stem cell(CSC) marker Cd44 compared to parental cells grown as adherent cultures.We report that epithelial markers E-cadherin and ZO-1 were downregulated,while mesenchymal markers Vimentin and Fibronectin were upregulated in 3-dimensional spheres.The 3-dimensional spheres also exhibited changes in expression of Snai,Zeb and Twist family of EMT transcription factors.CONCLUSION Our novel method successfully enriched stem-like cells which possessed an EMT phenotype.The isolation and characterization of murine hepatic CSCs could establish a precise target for the development of more effective therapies for HCC.

Hepatocellular carcinoma and immunotherapy:Beyond immune checkpoint inhibitors

Hepatocellular carcinoma(HCC)is one of the deadliest and most common malignancies of the liver.Considering the rich immune background of carcinogenesis in HCC,efforts have been focused on further understanding the role of the immune system in tumor suppression and promotion.The utilization of immunotherapy in HCC has led to encouraging results that has translated to longer survival and better quality of life among patients.The development of novel HCC-tailored regimens such as vaccine therapy and adoptive cellular therapy coupled with a deeper understanding of biomarkers predictive of the response to immunotherapy will lead to better treatment outcomes.

Cryoablation Combined with TACE for Treating Large Hepatocellular Carcinoma： Tumor Load and Cellular Immunity

OBJECTIVE To study the effectiveness on the tumor load and cellular immune function of percutaneous cryoablation （argon-helium cryoablative system, AHCS） combined with transarterial chemoembolization （TACE） for treating large hepatocellular carcinomas （HCCs） with diameters over 10 ca. METHODS A total of 48 HCC patients were treated with AHCS after TACE. Tumor sizes ranged from 10 to 14 cm. All cases were a hypervascular type. There were 38 Child A cases and 10 Child B cases. Forty were AFP positive and 8 negative. The patients were randomized with therapy group consisting of 26 cases and the control group 22 cases. The therapy group received AHCS 4 weeks following TACE treatment. Reexamination included pathology, tumor markers, T-lymphocyte subgroup levels and computed tomography or MRI. The necrosis rate of the tumor load was calculated by Cavalieri＇s theory. EORTC QLQ-C30 was used in quality of life evaluation. RESULTS The average tumor-load reduction rate （necrosis rate） was 8.07% after TACE, and 28.65% after AHCS. Coagulation necrosis was produced in the target area. The tumor markers deceased significantly after AHCS. Tumor-load reduction after AHCS was more significant than after TACE. Suppression of cellular immunity after TACE was significant. In contrast, CD3^＋, CD4^＋ and NK increased after AHCS and an abnormal T-lymphocyte distribution was corrected. Quality of life after AHCS increased according to the EORTC QLQ-C30 evaluation. No severe complications occurred. CONCLUSION Percutaneous AHCS cryoablation after TACE reduced the tumor load in the short term. At the same time, cellular immune function was increased after AHCS. TACE was critical in increasing the therapeutic efficacy of AHCS because of its embolisation of blood vessels preventing a Flow Effect. Reduction of the tumor load in the short term may conduce to increase cellular immunity. Percutaneous AHCS cryoablation combined with TACE can reduce the tumor load, improve cellular immunity and increase quality of life of HCC patients. This type of therapy deserves to be studied further research.

EXPRESSION OF CELLULAR ONCOGENES IN HUMAN PRIMARY HEPATOCELLULAR CARCINOMA

With DNA-mRNA hybridization in situ technique, the expression of five oncogenes, c-N-ras, c-Ki-ras. c-Ha-ras, c-myc and c-fos, was observed in two cases of human hepatocellular carcinoma. The expression of c-N-ras & c-fos was greatly enhanced in tumor tissues of the two cases, and about 25% -50% of the tumor cells showed positive expression. The other three oncogenes namely c-Ki-ras, c-Ha-ras & c-myc, were not detected in these two carcinomas or in the non-cancerous liver tissues adjacent to the carcinomas. It is surmised that c-N-ras and c-fos may play coordinative role in maintaining the malignant phenotype of human primary hepatocellular carcinoma.

Hepatocellular carcinoma occurring in a Crohn’s disease patient

We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn’s disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the nonneoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.

Cellular senescence throws new insights into patient classification and pharmacological interventions for clinical management of hepatocellular carcinoma

BACKGROUND Cellular senescence,a state of stable growth arrest,is intertwined with human cancers.However,characterization of cellular senescence-associated phenotypes in hepatocellular carcinoma(HCC)remains unexplored.AIM To address this issue,we delineated cellular senescence landscape across HCC.METHODS We enrolled two HCC datasets,TCGA-LIHC and International Cancer Genome Consortium(ICGC).Unsupervised clustering was executed to probe tumor heterogeneity based upon cellular senescence genes.Least absolute shrinkage and selection operator algorithm were utilized to define a cellular senescence-relevant scoring system.TRNP1 expression was measured in HCCs and normal tissues through immunohistochemistry,immunoblotting and quantitative real-time polymerase chain reaction.The influence of TMF-regulated nuclear protein(TRNP)1 on HCC senescence and growth was proven via a series of experiments.RESULTS TCGA-LIHC patients were classified as three cellular senescence subtypes,named C1–3.The robustness and reproducibility of these subtypes were proven in the ICGC cohort.C2 had the worst overall survival,C1 the next,and C3 the best.C2 presented the highest levels of immune checkpoints,abundance of immune cells,and immunogenetic indicators.Thus,C2 might possibly respond to immunotherapy.C2 had the lowest somatic mutation rate,while C1 presented the highest copy number variations.A cellular senescence-relevant gene signature was generated,which can predict patient survival,and chemo-or immunotherapeutic response.Experimentally,it was proven that TRNP1 presented the remarkable upregulation in HCCs.TRNP1 knockdown induced apoptosis and senescence of HCC cells and attenuated tumor growth.CONCLUSION These findings provide a systematic framework for assessing cellular senescence in HCC,which decode the tumor heterogeneity and tailor the pharmacological interventions to improve clinical management.

Association of the Cellular Apoptosis Susceptibility Protein with HBV Infection in Hepatocellular Carcinoma

Objective The cellular apoptosis susceptibility(CAS) protein plays a regulatory role in the induction of cell death in tumor cells. The objective of this study was to investigate the association of the expression of CAS protein with HBV infection in the development of HCC. Methods The expression level of CAS was measured with immunohistochemistry. The occurrence of HBs Ag, HBe Ag and HBV DNA in HCC were concurrently examined with immunohistochemistry and in situ hybridization, respectively. Results The results showed that the CAS protein was detected in 86%(43/50), 70%(7/10), 15%(3/20) and none(0/20) of livers from patients with HCC, cholangiocarcinoma, cirrhosis and hepatitis, respectively. Furthermore, the level of CAS protein was higher in poorly differentiated tumors than moderately or well differentiated HCC. Interestingly, the CAS was stained significantly stronger in HBV-infected HCC than in non-HBV infected tissues(P < 0.01). Conclusions The expression of CAS is facilitated by HBV infection in HCC, suggesting that CAS might be a prognostic marker and a putative therapeutic target for HCC.

MiR-25-3p attenuates the proliferation of tongue squamous cell carcinoma cell line Tca8113

Objective:To investigate the effects of miR-25-3p on the occurrence,development and proliferation of tongue squamous cell carcinoma cells.Methods:To establish tongue squamous cell carcinoma cell line Tca8113 that stably and highly express miR-25-3p using recombinant reiroviral vector-mediated gene transfer method.The proliferation of transfected Tca8113 was detected by thiazolyl blue tetrazolium bromide(MTT)and cell colony formation assays.eyclnD1,p21^(cipt)and p27^(kipt)mRNA expressions in the transfected Tca-8113 were detected by quantitative PCR.cyclinD1,p21^(cipt),p27^(kipt),AKT,p-AKT,FOXOt and p-FOX01 expressions in the transfected Tca8113 were detected by western blot analysis.In addition,miR-25-3p expression in the tongue squamous cell carcinoma cell line and tissue specimen was also detected by quantitative PCR.Results:Quantitative PCR showed that mitt-25-3p expression in the tongue squamous cell carcinoma cell lines and tissue specimen was significantly lower than that in the adjacent tissue.MTT and cell colony formation assays showed that after miR-25-3p overexpression,the proliferation of transfected Tca8113 was obviously attenuated.Western blot analysis and quantitative PCR showed that after miR-25-3p overexpression.p21^(cipt)and p27^(kipt)expressions were upregulated,while cyclinD1,AKT,FOXO1 expressions were downregulated,and AKT and FOXO1 phosphorylation was inactivated in the transfected Tca8113 cells.Conclusions:MiR-25-3p inhibited the proliferation of tongue squamous cell carcinoma cells and regulated cell cycle-related protein expression,playing an important role in the occurrence and development of squamous cell carcinoma of the tongue.

IMMUNOLOGIC CHARACTER OF TUMOR INFILTRATING LYMPHOCYTES IN OVARIAN CARCINOMA

Objective: To study immunologic character of tumor-infiltrating lymphocytes (TIL) on postin vitro expansion in ovarian carcinoma, and evaluate the prospects by adopting TIL treatment of ovarian carcinoma at an advanced stage. Methods: Cellular phenotype changes in TIL were analyzed by flow cytometry. By means of molecular biology and immunologic methods, ability to secrete cytokines and anti-tumor activities of in TIL was studied. Results: Difference of cellular phenotypes in TIL was probably related to the type, feature and resource of the tumor. TIL obtained from phoroplast and parenchyma was dominant in CD3+CD4+. TIL obtained from tumor tissues, around microvessels and ascitic fluid was dominant in CD3+CD8 Concentration of rIL-2in vitro played a significant role in immunologic character of TIL. By means of rIL-2 expansionin vitro, TIL has apparently been improved in competence of secreting some cytokines, such as IL-2, TNF-α, IFN-γ, and anti-tumor activities. The activated TIL was more stimulated by further adding anti-CD3 or PHA (suitable concentration), which significantly increased its ability to secrete cytokines. Treatment with TIL+CTX or TIL+ rIL-2, could apparently improve phenotypes in peripheral blood of patients, with definitive effects. Conclusion: Immunologic activities of TILin vitro are apparently improved by rIL2 expansion. Regression of tumor, by means of infusion TIL, is not largely attributed to direct cytotoxicity to tumor cells, but indirectly and partly augmenting cellular activities and abilities of immunomodulation in patients with ovarian carcinoma being dependent on secreting multiple cytokines.

BRMS1 performs an anti-tumor effect on renal cell carcinoma via inhibition of PI3K/AKT/mTOR signaling pathway

Objective:To explore the anti-tumor of breast cancer metastasis suppressor 1(BRMS1)on renal cell carcinoma.Methods:BRSM1 stabilized overexpressed and knockdown cell models were constructed to detect the effect of BRMS1 overexpression and knockdown on viability rate of 769-P cells.Activation of PI3K/AKT-mTOR-NFκB signaling pathway,expression of cellular apoptosis-related proteins,DNA damage repair-related proteins and angiogenesis-related proteins were detected using Western blotting analysis.Results:The viability rate of 769-P cells were significantly decreased in BRMS1 overexpression cells while significantly increased in BRMS1 knockdown cells(P<0.05).The activity of PI3K/AKT-mTOR-NFκB signaling pathway was significantly inhibited with BRMS1 overexpression(P<0.05),and expression of BAX was significantly increased with significantly decreased expression of Bcl-2(P<0.05).Besides,BRMS1 overexpression could significantly decrease the expression of DNA damage repair-related proteins and angiogenesis and cell-matrix degradation related proteins(P<0.05).Conclusion:BRMS1 induces apoptosis of renal cell carcinoma and performs an anti-tumor effect via inhibition of PI3K/AKT-mTOR-NFκB signaling pathway,expression of DNA damage repair-related proteins and angiogenesis-related proteins.

Mechanism of Moxibustion Regulation on Cellular Apoptosis in Rat's Precancerous Lesion of Primary Hepatocellular Carcinoma

Objective： To investigate the mechanism of moxibustion in regulating cellular apoptosis in rat＇s precancerous lesion of primary hepatocellular carcinoma （HCC）. Methods： Seventy-four rats were randomly allocated to normal group, model group and moxibustion group, and the diethylic nitrosamine （DEN） was used to establish HCC model. Moxibustion with moxa cone which is as big as a grain of wheat was performed on acupoint Zusanli （ST 36）, 3 cones for each acupoint and 0.5 mg for each cone, the treatment was given once a day, totally 16 weeks. Then the changes in the body weight, liver weight and thymus weight, a morphological change in the liver tissue and changes in γ-GT and GST were observed; Immunohistochemical staining method was adopted to observe the tendency of changes in relevant apoptosis genes such as C-myc, N-ras and mutant type P53, and the influence of moxibustion on cell cycle modulation genes such as cyclinD1, CDK4 and pl6. Results： Moxibustion could reduce the activities of γ-GT and GST in the blood, obviously decrease the protein expression of relevant apoptosis genes such as C-myc, N-ras and mutant type P53 and markedly inhibit the over-expression of relevant cell cycle modulation genes such as cyclinD1 and CDK4 and the mutation of cell cycle modulation gene pl 6. Conclusion： Moxibustion might play a certain role in relieving HCC precancerous lesion and its action mechanism might be related to the regulation on partial apoptosis genes.

A bystander cell-based GM-CSF secreting vaccine synergized with a low dose of cyclophosphamide presents therapeutic immune responses against murine hepatocellular carcinoma

Granulocyte-macrophage colony-stimulating factor （GM-CSF） secreting cellular tumor vaccines contribute to the induction of potent antitumor immune responses in murine models and patients suffering from cancers. Hepatocellular carcinoma （HCC） is one of the most frequent and malignant cancers in China. We describe, for the first time, a GM-CSF releasing vaccine strategy that represents a step toward combating this type of cancer. In this study, a bystander cell-based GM-CSF secreting vaccine against murine HCC, Hepa 1-6/B78H 1-GM-CSF, was co-administered with a low dose of cyclophosphamide （CY）. After challenging with tumor and vaccination, immunological assays demonstrated that the cellular antitumor immune responses were efficiently activated and that tumor development was significantly retarded, which was dependent on synergy with CY. The promising outcome of the anti-HCC vaccine in the murine model demonstrates the feasibility of a future clinical application for this treatment in HCC patients.

Gold Standard for Skin Cancer Treatment: Surgery (Mohs) or Microscopic Molecular-Cellular Therapy (Curaderm)?

Non-melanoma skin cancers or keratinocyte cancers such as basal cell carcinoma and squamous cell carcinoma make up approximately 80% and 20% respectively, of skin cancers with the 6 million people that are treated annually in the United States. 1 in 5 Americans and 2 in 3 Australians develop skin cancer by the age of 70 years and in Australia it is the most expensive, amassing $1.5 billion, to treat cancers. Non-melanoma skin cancers are often self-detected and are usually removed by various means in doctors’ surgeries. Mohs micrographic surgery is acclaimed to be the gold standard for the treatment of skin cancer. However, a novel microscopic molecular-cellular non-invasive topical therapy described in this article, challenges the status of Mohs procedure for being the acclaimed gold standard.