Want to Cure Cancer? Then Revisit the Past;“Warburg Was Correct”, Cancer Is a Metabolic Disease

I want to make it very clear at the beginning of this communication;this is a controversial opinion review. However, I believe it is time to rethink our approach to cancer research and therapy. Many cancer researchers, especially those involved in cancer genomic research will disagree. I welcome the disagreement and hope it will stimulate an honest debate and dialog between all disciplines of cancer research and treatment. I am convinced that a vast disconnection exists between those involved in basic research and those in the clinical arena that treat this disease. Cancer researchers in all areas should not ignore the role of cancer metabolism in tumorigenesis, progression and metastasis.

Cancer: Tumor Iron Metabolism, Mitochondrial Dysfunction and Tumor Immunosuppression;“A Tight Partnership—Was Warburg Correct?”

Over the last 30 years there have been numerous worldwide investigators involved in cancer research. Billions of dollars have been spent on drug development and cancer research;however, with all of the new agents and modalities of treatment, we have honestly not significantly improved the overall survival of the Stage IV cancer patient. There is and will not be a magic bullet treatment, thus the extensive title of this paper. We are convinced that unless we use multiple innovative therapies in combination with conventional treatment, we will never truly defeat this disease. We have attempted to address this problem by presenting in detail some of these complex mechanisms involved in tumorigenesis, progression, escape, and metastasis. Most investigators have their own special area of interest, but if we are to conquer this scourge, we must develop an extensive, multifaceted, comprehensive approach. Hopefully this article will contribute to awareness and further insight into this very serious and complicated problem, so we can improve quality of life and improve the survival of the Stage IV cancer patient.

Mitochondria Dynamically Transplant into Cells in Vitro and in Mice and Rescue Aerobic Respiration of Mitochondrial DNA-Depleted Motor Neuron NSC-34

It has been reported that transplantation of pheochromocytoma P12 and hepatoma cells’ mitochondria improve the locomotive activity and prevent disease progress in experimental Parkinson’s disease rats. To prepare for mitochondrial transplantation study in human neurodegenerative diseases, we select human fibroblasts as mitochondrial donor because that fibroblasts share many characteristics with mesenchymal stromal cells (MSCs). We isolate human primary fibroblasts and develop a mitochondrial DNA (mtDNA)-depleted mouse motor neuron NSC-34 cells (NSC-34 ρ° cells). Fibroblast and NSC-34 cell’s mitochondria are co-cultured with NSC-34 ρ° cells. Mitochondrial transplantation is observed by fluorescent microscopy. Gene expression is determined by polymerase chain reaction (PCR) and real time PCR (qPCR). Also, mitochondria are injected to mice bearing mammary adenocarcinoma 4T1 cells. We find results as following: 1) There are abundant mitochondria in fibroblasts (337 ± 80 mitochondria per fibroblast). 42.4% of viable mitochondria are obtained by using differential centrifugation. The isolated mitochondria actively transplant into NSC-34 ρ° cells after co-culture. 2) Fibroblasts transfer mitochondria to human mammary adenocarcinoma MCF-7 cells. 3) There is no expression of HLA-I antigen in fibroblast’s mitochondria indicating they can be used for allogeneic mitochondrial transplantation without HLA antigen match. 4) PCR and qPCR show that NSC-34 ρ° cells lose mitochondrially encoded cytochrome c oxidase I (MT-CO1) and mitochondrially encoded NADH dehydrogenase 1 (MT-ND1) and upregulate expression of glycolysis-associated genes hexokinase (HK2), glucose transporter 1 (SLC2A1) and lactate dehydrogenase A (LDHA). 5) Transplantation of NSC-34 mitochondria restores MT-CO1 and MT-ND1 and downregulates gene expression of HK2, SLC2A1 and LDHA. 6) Normal mammary epithelial mitochondria successfully enter to 4T1 cells in mice. Subcutaneous injection of mitochondria is safe for mice. In summary, mitochondrial transplantation replenishes mtDNA and rescues aerobic respiration of diseased cells with mitochondrial dysfunction. Human primary fibroblasts are potential mitochondrial donor for mitochondrial transplantation study in human neurodegenerative diseases.

Antibiotics Friend and Foe: “From Wonder Drug to Causing Mitochondrial Dysfunction, Disrupting Human Microbiome and Promoting Tumorigenesis”

Mitochondria are evolutionary bacteria that are dynamic intracellular organelles involved in many vital cellular functions. However, modern medicine has fallen prey to misuse and over-usage of antibiotics. This misuse can damage the mitochondrion, alter host antibiotic interactions, and cause serious pathophysiologic conditions. We believe this leads to mitochondrial dysfunction, which may promote tumorigenesis and neurodegeneration. This opinion commentary’s goal is to bring awareness of this important hot topic to the medical community before induced modern plagues are irreversible.

Initial Experience with Contrast Enhanced Digital Mammography (SenoBright)—In a Comprehensive Clinical Breast Center

Objective: The purpose of initiating contrast enhanced digital mammography in our center was to evaluate the complimentary benefit of this technology with screening digital mammography and real time ultrasound in equivocal cases and high risk patients with dense breast. The intended goal was to reduce the incidence of further diagnostic and invasive procedures. Methods: Patients thought to be candidates who had good renal function confirmed by serum Blood Urea Nitrogen (BUN) and Creatinine were offered the procedure, and 225 patients had the procedure during the period of March 2013 through November 2014. The contrast enhanced digital mammograms (SenoBright) are performed on the Senograph Essential Unit. A total of 8 images are obtained: 4 conventional digital mammograms and 4 contrast enhanced digital mammograms. The patients with a positive SenoBright study had a tissue diagnosis of the lesion obtained by either a stereotactic needle biopsy, ultrasound guided core biopsy, or ultrasound directed open excisional biopsy. Results: The 225 patients who had the procedure included high risk patients with dense breast (41), patients with abnormal mammograms (92), and patients with equivocal clinical, mammographic and real time ultrasound findings (92). 31 studies were interpreted as positive and 194 as negative. 33 biopsies were performed, with 31 patients having a positive study and 2 patients with a negative study. 22 cancers were detected. Conclusion: We found that the addition of dynamic contrast enhanced digital subtraction mammography (SenoBright) was helpful in distinguishing malignant from non-malignant lesions. It was also effective in demonstrating multifocal lesions and identifying non-palpable occult carcinomas in the dense breast. It proved to be a valuable complimentary adjunctive diagnostic modality for a comprehensive clinical breast center.

Breast and Ovarian Carcinoma Overexpress HLA-G, a Neglected Cancer Immunosuppressive Protein

Purpose: HLA-G binds to the inhibitory receptors of uterine NK cells and plays an important role in protection of fetal cells from maternal NK lysis. HLA-G also mediates tumor escape, but the immunosuppressive role is often neglected. These studies have focused on the examination of HLA-G expression in human breast and ovarian carcinoma and HLA-G immunosuppressive role in NK cytolysis. Methods: We examined HLA-G expression in breast and ovarian carcinoma cell lines by real time PCR, ELISA and immunofluorescent staining, and in frozen breast and ovarian carcinoma tissues by immunohistochemistry (IHC). We treated the breast cancer cell lines with anti-human HLA-G antibody or progesterone. Then, NK cytolysis was measured by using MTT assay. Results: We find breast and ovarian cancer cell lines increase the expression of HLA-G mRNA and protein, compared to normal cells. IHC shows that 100% of frozen breast and ovarian carcinoma tissues overexpress HLA-G protein. HLA-G IHC scores of breast and ovarian carcinoma are significantly higher than normal breast and ovarian tissues, respectively (both p < 0.01). Blocking HLA-G of the breast cancer cells by the antibody increases NK cytolysis. Progesterone upregulates HLA-G mRNA and protein of human breast cancer cell lines. The increased HLA-G expression by progesterone suppresses the NK cytolysis. Conclusion: Human breast and ovarian carcinoma overexpress HLA-G immunosuppressive molecules. Blocking HLA-G protein by antibody improves the cytolysis of NK cells against human breast cancer cell lines. In contrast, upregulation of HLA-G expression by progesterone impairs NK cytolytic function. Thus, HLA-G is a new immune checkpoint protein and potential cancer immunotherapeutic target.