RESUMO
BACKGROUND: High oxidative stress as defined by hydroxyl and peroxyl activity is often found in the stroma of human breast cancers. Oxidative stress induces stromal catabolism, which promotes cancer aggressiveness. Stromal cells exposed to oxidative stress release catabolites such as lactate, which are up-taken by cancer cells to support mitochondrial oxidative phosphorylation. The transfer of catabolites between stromal and cancer cells leads to metabolic heterogeneity between these cells and increased cancer cell proliferation and reduced apoptosis in preclinical models. N-Acetylcysteine (NAC) is an antioxidant that reduces oxidative stress and reverses stromal catabolism and stromal-carcinoma cell metabolic heterogeneity, resulting in reduced proliferation and increased apoptosis of cancer cells in experimental models of breast cancer. The purpose of this clinical trial was to determine if NAC could reduce markers of stromal-cancer metabolic heterogeneity and markers of cancer cell aggressiveness in human breast cancer. METHODS: Subjects with newly diagnosed stage 0 and I breast cancer who were not going to receive neoadjuvant therapy prior to surgical resection were treated with NAC before definitive surgery to assess intra-tumoral metabolic markers. NAC was administered once a week intravenously at a dose of 150 mg/kg and 600 mg twice daily orally on the days not receiving intravenous NAC. Histochemistry for the stromal metabolic markers monocarboxylate transporter 4 (MCT4) and caveolin-1 (CAV1) and the Ki67 proliferation assay and TUNEL apoptosis assay in carcinoma cells were performed in pre- and post-NAC specimens. RESULTS: The range of days on NAC was 14-27 and the mean was 19 days. Post-treatment biopsies showed significant decrease in stromal MCT4 and reduced Ki67 in carcinoma cells. NAC did not significantly change stromal CAV1 and carcinoma TUNEL staining. NAC was well tolerated. CONCLUSIONS: NAC as a single agent reduces MCT4 stromal expression, which is a marker of glycolysis in breast cancer with reduced carcinoma cell proliferation. This study suggests that modulating metabolism in the tumor microenvironment has the potential to impact breast cancer proliferation.
Assuntos
Acetilcisteína/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Sequestradores de Radicais Livres/uso terapêutico , Mastectomia , Adulto , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Caveolina 1/metabolismo , Proliferação de Células , Feminino , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Terapia Neoadjuvante , Estadiamento de Neoplasias , Projetos Piloto , Células Estromais/metabolismo , Resultado do Tratamento , Microambiente TumoralRESUMO
OBJECTIVES/HYPOTHESIS: In many cancers, varying regions within the tumor are often phenotypically heterogeneous, including their metabolic phenotype. Further, tumor regions can be metabolically compartmentalized, with metabolites transferred between compartments. When present, this metabolic coupling can promote aggressive behavior. Tumor metabolism in papillary thyroid cancer (PTC) is poorly characterized. STUDY DESIGN: Immunohistochemical staining of tissue samples. METHODS: Papillary thyroid cancer specimens from 46 patients with (n = 19) and without advanced disease (n = 27) were compared to noncancerous thyroid tissue (NCT) and benign thyroid specimens (n = 6 follicular adenoma [FA] and n = 5 nodular goiter [NG]). Advanced disease was defined as the presence of lateral neck lymphadenopathy. Immunohistochemistry was performed for translocase of outer mitochondrial membrane 20 (TOMM20), a marker of oxidative phosphorylation, and monocarboxylate transporter 4 (MCT4), a marker of glycolysis. RESULTS: Papillary thyroid cancer and FA thyrocytes had high staining for TOMM20 compared to NCT and nodular goiter (NG) (P < 0.01). High MCT4 staining in fibroblasts was more common in PTC with advanced disease than in any other tissue type studied (P < 0.01). High MCT4 staining was found in all 19 cases of PTC with advanced disease, in 11 of 19 samples with low-stage disease, in one of five samples of FA, in one of 34 NCT, and in 0 of six NG samples. Low fibroblast MCT4 staining in PTC correlated with the absence of clinical adenopathy (P = 0.028); the absence of extrathyroidal extension (P = 0.004); low American Thyroid Association risk (P = 0.001); low AGES (age, grade, extent, size) score (P = 0.004); and low age, metastasis, extent of disease, size risk (P = 0.002). CONCLUSION: This study suggests that multiple metabolic compartments exist in PTC, and low fibroblast MCT4 may be a biomarker of indolent disease. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:2410-2418, 2016.
Assuntos
Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/fisiologia , Carcinoma/metabolismo , Compartimento Celular/fisiologia , Neoplasias da Glândula Tireoide/metabolismo , Adenoma/metabolismo , Adulto , Idoso , Carcinoma Papilar , Estudos de Casos e Controles , Feminino , Bócio Nodular/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Proteínas de Membrana Transportadoras/análise , Pessoa de Meia-Idade , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Transportadores de Ácidos Monocarboxílicos/análise , Proteínas Musculares/análise , Receptores de Superfície Celular/análise , Câncer Papilífero da Tireoide , Adulto JovemRESUMO
A patient diagnosed with metastatic melanoma developed the paraneoplastic syndrome of humoral hypercalcemia of malignancy and cachexia after receiving ipilumumab. The cause of the hypercalcemia was thought to be secondary to parathyroid hormone-related peptide (PTHrP) as plasma levels were found to be elevated. The patient underwent two tumor biopsies: at diagnosis (when calcium levels were normal) and upon development of hypercalcemia and cachexia. PTHrP expression was higher in melanoma cells when hypercalcemia had occurred than prior to its onset. Metabolic characterization of melanoma cells revealed that, with development of hypercalcemia, there was high expression of monocarboxylate transporter 1 (MCT1), which is the main importer of lactate and ketone bodies into cells. MCT1 is associated with high mitochondrial metabolism. Beta-galactosidase (ß-GAL), a marker of senescence, had reduced expression in melanoma cells upon development of hypercalcemia compared to pre-hypercalcemia. In conclusion, PTHrP expression in melanoma is associated with cachexia, increased cancer cell lactate and ketone body import, high mitochondrial metabolism, and reduced senescence. Further studies are required to determine if PTHrP regulates cachexia, lactate and ketone body import, mitochondrial metabolism, and senescence in cancer cells.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Hipercalcemia/metabolismo , Melanoma/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Anticorpos Monoclonais/efeitos adversos , Caquexia/induzido quimicamente , Feminino , Humanos , Hipercalcemia/induzido quimicamente , Ipilimumab , Melanoma/patologia , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/metabolismo , Síndromes Paraneoplásicas/induzido quimicamente , Simportadores/metabolismoRESUMO
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.