Idiopathic nodular glomerulosclerosis in a chronic marijuana user; a case report and review of the literature

Background: Nodular glomerulosclerosis is a characteristic histological finding of diabetic nephropathy (DN) with thickened glomerular basement membrane (GBM) and hyalinized arterioles. Idiopathic nodular glomerulosclerosis (ING), a rare distinct clinicopathologic entity, is the term used to denote classic DN confirmed by light microscopy, immuno-fluorescence, and electron microscopy in the absence of diabetes mellitus (DM). ING has been linked to heavy tobacco smoking, chronic hypertension, obesity and insulin resistance. Its association with marijuana use is unknown. Case Presentation: We report a case of biopsy-proved ING in the absence of pre-existing history of DM and heavy smoking. This report addresses the possible accentuation of tobacco use risk by marijuana. Conclusions: This report addresses the possible accentuation of tobacco use risk by marijuana. © 2017 The Author(s); Published by Society of Diabetic Nephropathy Prevention

FOXD3 Regulates VISTA Expression in Melanoma.

Immune checkpoint inhibitors have improved patient survival in melanoma, but the innate resistance of many patients necessitates the investigation of alternative immune targets. Many immune checkpoint proteins lack proper characterization, including V-domain Ig suppressor of T cell activation (VISTA). VISTA expression on immune cells can suppress T cell activity; however, few studies have investigated its expression and regulation in cancer cells. In this study, we observe that VISTA is expressed in melanoma patient samples and cell lines. Tumor cell-specific expression of VISTA promotes tumor onset in vivo, associated with increased intratumoral T regulatory cells, and enhanced PDL-1 expression on tumor-infiltrating macrophages. VISTA transcript levels are regulated by the stemness factor Forkhead box D3 (FOXD3). BRAF inhibition upregulates FOXD3 and reduces VISTA expression. Overall, this study demonstrates melanoma cell expression of VISTA and its regulation by FOXD3, contributing to the rationale for therapeutic strategies that combine targeted inhibitors with immune checkpoint blockade

Stromal Monocarboxylate Transporter MCT4 is a Poor Prognostic Factor in Squamous Cell Carcinoma

ABSTRACT Introduction: Monocarboxylate transporter 4 (MCT4) is the main exporter of lactate out of cells. It is also a critical component in the glycolytic metabolism of cancer cells. In this study, stromal MCT4 in oral SCC was correlated with risk of recurrence (ROR), extent of primary tumor (pT) and nodal metastasis (pN), perineural invasion (PNI), lymphovascular invasion (LVI), HPV status, extracapsular extension (ECE) and positive margin. Methods: Clinical data were collected for 86 consecutive patients with oral HNSCC. Tissue microarrays (TMA) were constructed from paraffin blocks of resection specimens and stained for MCT4. Immunohistochemistry (IHC) staining was assessed and quantified by digital image analysis with Aperio software. Using a co-localization algorithm we assessed the intensity of staining and the percentage of positive cells in the tumoral stromal cells. Correlations of MCT4 expression with clinicopathological features and survival were studied. Results: Increased IHC staining for MCT4 was strongly associated with an increased risk of recurrence, OR 1.96 (95%CI: 1.17-3.40), presence of PNI, OR 2.25 (95%CI: 1.33-3.95), higher pT, OR 1.68 (95%CI: 0.99-2.89), higher pN, OR 2.07 (95%CI: 1.25-3.57) and presence of LVI, OR 2.21 (95%CI: 1.11-4.67). We didn’t find any significant association between stromal MCT4 expression and HPV status, presence of ECE or positive margin. Conclusions: This study demonstrates that MCT4, a marker of glycolysis in cancer-associated stroma, is highly expressed in oral SCC. The IHC staining pattern of stromal MCT4 suggests that high MCT4 expression appears to be a useful marker for tumor progression and prognosis. We propose MCT4 serves as a new prognostic factor in oral SCC and can act as a potential therapeutic target marker considering pharmacological development of MCT4 inhibitors

MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer.

Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. Methods: MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or progesterone receptor positive (ER+ and/or PR+), 62 cases were human epidermal growth factor receptor 2 positive (HER2+), and 56 cases were triple negative breast cancers (TNBC). MCT1 expression was quantified by digital pathology with Aperio software. The intensity of the staining was measured on a continuous scale (0-black to 255-bright white) using a co-localization algorithm. Statistical analysis was performed using a linear mixed model. Results: High MCT1 expression was more commonly found in TNBC compared to ER+ and/or PR+ and compared to HER-2+ (p \u3c 0.001). Tumors with an in-situ component were less likely to stain strongly for MCT1 (p \u3c 0.05). High nuclear grade was associated with higher MCT1 staining (p \u3c 0.01). Higher T stage tumors were noted to have a higher expression of MCT1 (p \u3c 0.05). High MCT1 staining in cancer cells was associated with shorter progression free survival, increased risk of recurrence, and larger size independent of TNBC status (p \u3c 0.05). Conclusion: MCT1 expression, which is a marker of high catabolite uptake and mitochondrial metabolism, is associated with recurrence in breast invasive ductal carcinoma. MCT1 expression as quantified with digital image analysis may be useful as a prognostic biomarker and to design clinical trials using MCT1 inhibitors

Tumor Metabolism in the Microenvironment of Nodal Metastasis in Head and Neck Squamous Cell Carcinoma

ABSTRACT Introduction: Monocarboxylate transporter 4 (MCT4) is a cell membrane transporter of lactate. MCT4 is a tumor-specific marker of oxidative stress, glycolysis and hypoxia in tumor stromal cells. We investigated HPV positive and negative tumors with regional metastases to cervical lymph nodes (LN) to study how the metastatic tumor cells interact with their microenvironment. By selecting cancers with extracapsular extension (ECE), we intended to evaluate the interaction between metastases and the surrounding extranodal tissue. Methods: Clinical data were collected from 24 advanced stage oropharyngeal squamous cell carcinoma (OPSCC) patients with neck LN metastasis. All patients presented with at least N1 disease and had ECE. Sixteen cases were negative for HPV and eight were positive. Ten patients (42%) had ECE \u3c 1 mm, and 14 (58%) had ECE \u3e than 1 mm. The extent of ECE was quantified on H&E stains by distance from the edge of capsule. The paraffin-embedded metastatic LN sections were stained with MCT4 and quantification was accomplished using the Aperio Co-localization algorithm. Results: High stromal MCT4 expression was strongly associated with the extent of ECE regardless of HPV status (p=0.031). The stromal MCT4 expression in ECE area was significantly higher as opposed to the surrounding extranodal tissue adjacent to intact capsule (p\u3c0.001). We also found a borderline difference in expression of MCT4 in HPV- LN with ECE \u3e1mm vs. \u3c1mm(p=0.06). Conclusions: MCT4 is a marker of oxidative stress and higher expression of stromal MCT4 in ECE area is significantly correlated with the extent of ECE. The stromal cells separating nests of cancer cells in ECE area have apparent expression of the MCT4. Together these findings provide new insight into the critical role of stromal MCT4 in nodal metastasis and ECE in OPSCC and it may be useful to develop a novel prognostic marker and new anti-cancer agents

Metformin Clinical Trial in HPV+ and HPV– Head and Neck Squamous Cell Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate

Background: Metformin, an oral anti-hyperglycemic drug which inhibits mitochondrial complex I and oxidative phosphorylation has been reported to correlate with improved outcomes in head and neck squamous cell carcinoma (HNSCC) and other cancers. This effect is postulated to occur through disruption of tumor-driven metabolic and immune dysregulation in the tumor microenvironment (TME). We report new findings on the impact of metformin on the tumor and immune elements of the TME from a clinical trial of metformin in HNSCC.Methods: Human papilloma virus—(HPV–) tobacco+ mucosal HNSCC samples (n = 12) were compared to HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples (n = 17) from patients enrolled in a clinical trial. Apoptosis in tumor samples pre- and post-treatment with metformin was compared by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Metastatic lymph nodes with extra-capsular extension (ECE) in metformin-treated patients (n = 7) were compared to archival lymph node samples with ECE (n = 11) for differences in immune markers quantified by digital image analysis using co-localization and nuclear algorithms (PD-L1, FoxP3, CD163, CD8).Results: HPV–, tobacco + HNSCC (mean Δ 13.7/high power field) specimens had a significantly higher increase in apoptosis compared to HPV+ OPSCC specimens (mean Δ 5.7/high power field) (p < 0.001). Analysis of the stroma at the invasive front in ECE nodal specimens from both HPV—HNSCC and HPV+ OPSCC metformin treated specimens showed increased CD8+ effector T cell infiltrate (mean 22.8%) compared to archival specimens (mean 10.7%) (p = 0.006). Similarly, metformin treated specimens showed an increased FoxP3+ regulatory T cell infiltrate (mean 9%) compared to non-treated archival specimens (mean 5%) (p = 0.019).Conclusions: This study presents novel data demonstrating that metformin differentially impacts HNSCC subtypes with greater apoptosis in HPV—HNSCC compared to HPV+ OPSCC. Moreover, we present the first in vivo human evidence that metformin may also trigger increased CD8+ Teff and FoxP3+ Tregs in the TME, suggesting an immunomodulatory effect in HNSCC. Further research is necessary to assess the effect of metformin on the TME of HNSCC

Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers

The most common cancers of the aerodigestive tract (ADT) are non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The tumor stroma plays an important role in ADT cancer development and progression, and contributes to the metabolic heterogeneity of tumors. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor stroma of ADT cancers and exert pro-tumorigenic functions. Metabolically, glycolytic CAFs support the energy needs of oxidative (OXPHOS) carcinoma cells. Upregulation of the monocarboxylate transporter 4 (MCT4) and downregulation of isocitrate dehydrogenase 3α (IDH3α) are markers of glycolysis in CAFs, and upregulation of the monocarboxylate transporter 1 (MCT1) and the translocase of the outer mitochondrial membrane 20 (TOMM20) are markers of OXPHOS in carcinoma cells. It is unknown if glycolytic metabolism in CAFs is a driver of ADT cancer aggressiveness. In this study, co-cultures in vitro and co-injections in mice of ADT carcinoma cells with fibroblasts were used as experimental models to study the effects of fibroblasts on metabolic compartmentalization, oxidative stress, carcinoma cell proliferation and apoptosis, and overall tumor growth. Glycolytic metabolism in fibroblasts was modulated using the HIF-1α inhibitor BAY 87-2243, the antioxidant N-acetyl cysteine, and genetic depletion of MCT4. We found that ADT human tumors express markers of metabolic compartmentalization and that co-culture models of ADT cancers recapitulate human metabolic compartmentalization, have high levels of oxidative stress, and promote carcinoma cell proliferation and survival. In these models, BAY 87-2243 rescues IDH3α expression and NAC reduces MCT4 expression in fibroblasts, and these treatments decrease ADT carcinoma cell proliferation and increase cell death. Genetic depletion of fibroblast MCT4 decreases proliferation and survival of ADT carcinoma cells in co-culture. Moreover, co-injection of ADT carcinoma cells with fibroblasts lacking MCT4 reduces tumor growth and decreases the expression of markers of metabolic compartmentalization in tumors. In conclusion, metabolic compartmentalization with high expression of MCT4 in CAFs drives aggressiveness in ADT cancers