Jennifer Maria Johnson

Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis

Background. Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147. Methods. We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses. Results. Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival (p < 0.001 for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival (p < 0.0001 for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival. Conclusion. MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations.

Metformin effects on head and neck squamous carcinoma microenvironment: window of opportunity trial

The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors.

Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target.

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 < 0.001). Tumors with an in-situ component were less likely to stain strongly for MCT1 (p < 0.05). High nuclear grade was associated with higher MCT1 staining (p < 0.01). Higher T stage tumors were noted to have a higher expression of MCT1 (p < 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 < 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.

Thyroid Cancer Metabolism: A Review

Metabolic dysregulation within the tumor microenvironment (TME) is critical to the process of tumorigenesis in various cancer types. Thyrocyte metabolism in papillary and anaplastic thyroid cancer, however, remains poorly characterized, and studies analyzing the role of multicompartment metabolism in thyrocyte oncogenesis are sparse. We present a review of the current knowledge on cellular metabolism in non-cancerous and cancerous thyroid tissues, focusing on the monocarboxylate transporters MCT1 and MCT4, and on a transporter of the outer mitochondrial membrane TOMM20. Understanding the metabolic phenotype of tumor cells and associated stromal cells in thyroid cancer can have profound implications on the use of biomarker staining in detecting subclinical cancer, imaging as it relates to expression of various transport proteins, and therapeutic interventions that manipulate this dysregulated tumor metabolism to halt tumorigenesis and eradicate the cancer. Future studies are required to confirm the prognostic significance of these biomarkers and their correlation with existing staging schemas such as the AGES, AMES, ATA and MACIS scoring systems.

Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies

Abstract Background Relapsed/metastatic salivary gland carcinomas (SGCs) have a wide diversity of histologic subtypes associated with variable clinical aggressiveness and response to local and systemic therapies. We queried whether comprehensive genomic profiling could define the tumor subtypes and uncover clinically relevant genomic alterations, revealing new routes to targeted therapies for patients with relapsed and metastatic disease. Patients and methods From a series of 85 686 clinical cases, DNA was extracted from 40 µm of formalin-fixed paraffin embedded (FFPE) sections for 623 consecutive SGC. CGP was carried out on hybridization-captured, adaptor ligation-based libraries (mean coverage depth, >500×) for up to 315 cancer-related genes. Tumor mutational burden was determined on 1.1 Mb of sequenced DNA. All classes of alterations, base substitutions, short insertions/deletions, copy number changes, and rearrangements/fusions were determined simultaneously. Results The clinically more indolent SGC including adenoid cystic carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma, mammary analog secretory carcinoma, and epithelial–myoepithelial carcinomas have significantly fewer genomic alterations, TP53 mutations, and lower tumor mutational burden than the typically more aggressive SGCs including mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified, carcinoma NOS, and carcinoma ex pleomorphic adenoma. The more aggressive SGCs are commonly driven by ERBB2 PI3K pathway genomic alterations. Additional targetable GAs are frequently seen. Conclusions Genomic profiling of SGCs demonstrates important differences between traditionally indolent and aggressive cancers. These differences may provide therapeutic options in the future.

A case of periampullary adenocarcinoma in neurofibromatosis type 1

Neurofibromatosis type 1 (NF-1) is an autosomal dominant genetic disorder with a known predisposition to gastrointestinal neoplasms such as stromal tumors and carcinoids. Adenocarcinomas (ACs) of the gastrointestinal tract are relatively rare in patients with NF-1, especially those found in the periampullary region. We present a case report of periampullary adenocarcinoma in a 56-year-old woman with NF-1 who presented with abdominal pain and obstructive jaundice.

Angiogenesis and Anti-angiogenic Therapy in Head and Neck Cancer

The formation of new blood vessels, or angiogenesis, takes place through a variety of different physiologic and unique pathologic processes in tumor tissue. While the control mechanisms of some of these processes are not yet understood, as in the case of de novo vessel formation or intussusceptive angiogenesis, a closer examination of the process of sprouting angiogenesis highlights the complexity of the molecular mechanisms of angiogenesis. Through both positive regulation with proteins such as vascular endothelial growth factors (VEGFs), fibroblast growth factor (FGF), and NOTCH and negative regulation with other signals such as thrombospondin, endostatin, and angiostatin, the endothelial cells of an existing vessel can reorganize into new functional luminal architecture. As our comprehension of the regulatory machinery has improved, so has the desire to create anti-angiogenic therapies using targeted monoclonal antibodies, tyrosine kinase inhibitors, and other novel targeted small molecular inhibitors directed at interrupting these regulatory signals. Drugs directed against vascular endothelial growth factors in particular (e.g., bevacizumab or sunitinib) have been studied as antineoplastic agents either alone or in combination with cytotoxic chemotherapy or other targeted agents. A unique toxicity profile has been seen with anti-angiogenics that may include events such as bleeding, hypertension, and proteinuria. The interest in targeting angiogenesis continues, and more clinical trials are underway with new targets and evolving strategies.

Molecular Profiling of Synchronous Colon Cancers and Anaplastic Thyroid Cancer in a Patient with Lynch Syndrome

Lynch syndrome is an autosomal dominant cancer susceptibility disorder caused by either a germ line mutation in a DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2 or deletion of the last few exons of the EPCAM gene leading to epigenetic silencing of MSH2 [1]. The deficient mismatch repair leads to a hyper mutated state as exemplified by microsatellite instability and eventual carcinogenesis. Clinically, the hallmark of Lynch syndrome is an increased predisposition to the development of colorectal cancers at a significantly younger age relative to their sporadic counterparts, metachronous and synchronous colonic primaries [1]. An increased frequency of neoplasia is also observed in the endometrium, ovary, upper urinary tract, stomach, hepatobiliary, pancreas, small intestine, brain/CNS, sebaceous glands, and keratoacanthomas [1]. Notably,MSH6mutations are associated with a higher proportion of extracolonic neoplasms, a later age of onset of these cancers, and a slightly lower risk of colorectal cancer [2, 3]. Thyroid carcinomas are not traditionally considered to be a part of the Lynch syndrome spectrum, and only two reports describe Lynch patients with thyroid cancer, both harboringMSH2 mutations and without synchronous colorectal carcinomas [4–6]. Recent data has linked tumors driven by microsatellite instability to response to immune-oncology approaches, such as anti-PD1 therapies [7, 8]. We describe here two synchronous colonic and an anaplastic thyroid carcinoma assessed by comprehensive genomic profiling (CGP) in the course of clinical care to demonstrate a hypermutated state thus presenting a potential therapeutic option for this unique clinical presentation.

Metformin as a Therapeutic Target in Endometrial Cancers.

Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer.