Diagnostic and Prognostic Value of ProEx C and GLUT1 in Melanocytic Lesions.

BACKGROUND: Melanoma is one of the most aggressive types of skin cancer. The purpose of this study was to evaluate the use of two biomarkers, ProEx C and glucose transporter isoform 1 (GLUT1), in the diagnosis and prognostication of melanoma. MATERIALS AND METHODS: We analyzed 129 melanomas and 59 benign nevi in a tissue microarray using immunohistochemical method with antibodies to topoisomerase IIα (TOP2A) and minichromosome maintenance complex component 2 (MCM2) using ProEx C and to GLUT1. RESULTS: The average proliferative index by ProEx C immunostain was significantly higher in melanomas (37.5%) compared to benign nevi (1.9%) as was the expression of GLUT1 (p<0.0001 respectively). Dermal mitosis was found to correlate positively with both ProEx C and GLUT1 (p=0.003 and p<0.001, respectively). Ulceration and tumor thickness positively correlated with GLUT1 expression (p=0.013 and p=0.033, respectively), but not with ProEx C staining. There was a significant association between increasing ProEx C index and stronger expression of GLUT1 (p<0.001). Kaplan-Meier disease-specific survival analyses indicated that patients whose melanoma exhibited expression of GLUT1 had a significantly lower rate of disease-specific survival than patients whose melanoma did not (p=0.039). However, staining by ProEx C did not show a prognostic significance in disease-specific survival. CONCLUSION: ProEx C and GLUT1 are potentially useful markers in differentiation of melanoma from nevi. Absence of GLUT1 expression in patients with primary melanoma predicts better survival.

A proof of principle clinical trial to determine whether conjugated linoleic acid modulates the lipogenic pathway in human breast cancer tissue.

Conjugated linoleic acid (CLA) is widely used as a "nutraceutical" for weight loss. CLA has anticancer effects in preclinical models, and we demonstrated in vitro that this can be attributed to the suppression of fatty acid (FA) synthesis. We tested the hypothesis that administration of CLA to breast cancer patients would inhibit expression of markers related to FA synthesis in tumor tissue, and that this would suppress tumor proliferation. Women with Stage I-III breast cancer were enrolled into an open label study and treated with CLA (1:1 mix of 9c,11t- and 10t,12c-CLA isomers, 7.5 g/d) for ≥ 10 days before surgery. Fasting plasma CLA concentrations measured pre- and post-CLA administration, and pre/post CLA tumor samples were examined by immunohistochemistry for Spot 14 (S14), a regulator of FA synthesis, FA synthase (FASN), an enzyme of FA synthesis, and lipoprotein lipase (LPL), the enzyme that allows FA uptake. Tumors were also analyzed for expression of Ki-67 and cleaved caspase 3. 24 women completed study treatment, and 23 tumors were evaluable for the primary endpoint. The median duration of CLA therapy was 12 days, and no significant toxicity was observed. S14 expression scores decreased (p = 0.003) after CLA administration. No significant change in FASN or LPL expression was observed. Ki-67 scores declined (p = 0.029), while cleaved caspase 3 staining was unaffected. Decrements in S14 or Ki-67 did not correlate with fasting plasma CLA concentrations at surgery. Breast tumor tissue expression of S14, but not FASN or LPL, was decreased after a short course of treatment with 7.5 g/day CLA. This was accompanied by reductions in the proliferation index. CLA consumption was well-tolerated and safe at this dose for up to 20 days. Overall, CLA may be a prototype compound to target fatty acid synthesis in breast cancers with a "lipogenic phenotype".

Tumor angiogenesis change estimated by using diffuse optical spectroscopic tomography: demonstrated correlation in women undergoing neoadjuvant chemotherapy for invasive breast cancer?

PURPOSE: To investigate if changes in tumor angiogenesis associated with complete pathologic response (pCR) or partial pathologic response (pPR) to treatment can be demonstrated by using diffuse optical spectroscopic (DOS) tomography. MATERIALS AND METHODS: All participants in this prospective, HIPAA-compliant, institutional review board-approved study provided written informed consent. Eleven women with invasive breast carcinoma were imaged with DOS tomography prior to, during, and at completion of neoadjuvant chemotherapeutic regimens. By using region of interest (ROI) analysis, the DOS measure of total tissue hemoglobin (Hb(T)) was temporally correlated with quantitative measures of existing (CD31-expressing) and tumor-induced (CD105-expressing) vessels, in pretreatment and posttreatment tissue specimens, to assess change. RESULTS: Quantified angiogenesis alone in pretreatment core biopsy specimens did not predict treatment response, but mean vessel density (MVD) and mean vessel area (MVA) of CD105-expressing vessels were significantly decreased in women with pCR (n = 7) (P < .001 and P = .003, respectively). MVA of CD105-expressing vessels was also significantly reduced at comparison of pre- and posttreatment residual tumor for women with pPR (n = 4) (P = .033). A longitudinal analysis showed significant decreases (P = .001) in mean Hb(T) levels during neoadjuvant chemotherapy in breast abnormality ROIs for women with pCR but not women with pPR. For women with pCR, but not women with pPR, pretreatment MVD of CD105-expressing vessels correlated with pretreatment Hb(T) (P ≤ .001). CONCLUSION: DOS tomographic examinations in women with breast cancer who are receiving neoadjuvant chemotherapy show a mean decrease in Hb(T) with time in patients with pCR only. Observed pretreatment and posttreatment correlates with quantified angiogenesis markers confirm the likely biologic origin for this DOS signature and support its potential to predict angiogenic tissue response early in the treatment cycle. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11100699/-/DC1.

Lipoprotein lipase links dietary fat to solid tumor cell proliferation.

Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA.