Stephen K. Lau

Inhibition of Breast Cancer Metastasis by Selective Synthetic Polypeptide against CXCR4

Metastasis shares many similarities with leukocyte trafficking. Among those chemokine receptors thought to be involved in hemopoietic cell homing, stromal cell-derived factor-1 and its receptor CXC chemokine receptor-4 (CXCR4) have received considerable attention. Like hemopoietic cell homing, levels of stromal cell-derived factor-1 are high at sites of breast cancer metastasis including lymph node, lung, liver, and the marrow. Moreover, CXCR4 expression is low in normal breast tissues and high in malignant tumors, suggesting that a blockade of CXCR4 might limit tumor metastasis. We therefore investigated the role of a synthetic antagonist 14-mer peptide (TN14003) in inhibiting metastasis in an animal model. Not only was TN14003 effective in limiting metastasis of breast cancer by inhibiting migration, but it may also prove useful as a diagnostic tool to identify CXCR4 receptor-positive tumor cells in culture and tumors in paraffin-embedded clinical samples.

Molecular Mapping of Tumor Heterogeneity on Clinical Tissue Specimens with Multiplexed Quantum Dots

Tumor heterogeneity is one of the most important and challenging problems not only in studying the mechanisms of cancer development but also in developing therapeutics to eradicate cancer cells. Here we report the use of multiplexed quantum dots (QDs) and wavelength-resolved spectral imaging for molecular mapping of tumor heterogeneity on human prostate cancer tissue specimens. By using a panel of just four protein biomarkers (E-cadherin, high-molecular-weight cytokeratin, p63, and alpha-methylacyl CoA racemase), we show that structurally distinct prostate glands and single cancer cells can be detected and characterized within the complex microenvironments of radical prostatectomy and needle biopsy tissue specimens. The results reveal extensive tumor heterogeneity at the molecular, cellular, and architectural levels, allowing direct visualization of human prostate glands undergoing structural transitions from a double layer of basal and luminal cells to a single layer of malignant cells. For clinical diagnostic applications, multiplexed QD mapping provides correlated molecular and morphological information that is not available from traditional tissue staining and molecular profiling methods.

Multiplexed Detection and Characterization of Rare Tumor Cells in Hodgkin’s Lymphoma with Multicolor Quantum Dots

The multicolor and multiplexing capabilities of semiconductor quantum dots (QDs) are most promising for improving the sensitivity and specificity of in vitro molecular and cellular diagnostics. Here, we report the use of multiplexed QDs and wavelength-resolved imaging to detect and characterize a class of low-abundant tumor cells in Hodgkins lymphoma. Known as the Hodgkins and Reed-Sternberg (HRS) cells, this class of malignant cells is a pathological hallmark in clinical diagnosis, but it comprises only about 1% of the heterogeneous infiltrating cells in lymph node tissues. To overcome this cellular heterogeneity and rarity problem, we have developed multicolor QD-antibody conjugates to simultaneously detect a panel of four protein biomarkers (CD15, CD30, CD45, and Pax5) directly on human tissue biopsies. This multiplexing approach allows rapid detection and differentiation of rare HRS cells from infiltrating immune cells such as T and B lymphocytes. We have also carried out clinical translation studies involving six confirmed Hodgkins lymphoma patients, two suspicious lymphoma cases, and two patients with reactive lymph nodes (but not lymphoma). The results indicate that a distinct QD staining pattern (CD15 positive, CD30 positive, CD45 negative, and Pax5 positive) can be used to not only detect Hodgkins lymphoma but also differentiate it from benign lymphoid hyperplasia.

Sox7 is an independent checkpoint for β-catenin function in prostate and colon epithelial cells

The presence of somatic β-catenin mutations in some prostate cancers implies that aberrant WNT signaling is involved in the cancer development. Although β-catenin stability is regulated by a multicomponent destruction complex, mutational alterations of β-catenin or other components of the destruction complexes are rare in prostate tumors. Therefore, β-catenin may be regulated by another protein in the prostate. In fact, recent linkage and somatic deletion analyses in prostate cancers reveal a 1.4-Mb candidate tumor suppressor locus on 8p23.1, which includes the Sox7 gene. Here we show that Sox7 protein expression was indeed down-regulated in 47% (15 of 32) of prostate adenocarcinomas. In addition, Sox7 mRNA was down-regulated in 60% of snap-frozen tumors. This down-regulation was found to be due to tumor-specific promoter hypermethylation, which was present in 48% (10 of 21) of primary prostate tumors and 44% (11 of 25) of prostate cancer cell lines/xenografts. We discovered that Sox7 protein physically interacts with β-catenin and suppresses β-catenin–mediated transcription by depleting active β-catenin. Furthermore, in HCT116 colorectal cancer cell lines with Sox7 inactivation, ectopic Sox7 expression suppressed cell proliferation and inhibited transcription that was activated by an endogenous mutant β-catenin. Although nearly all colorectal cancers contain mutations in β-catenin or adenomatous polyposis coli/axin, epigenetic silencing of Sox7 was still observed. These data suggest that Sox7 is a tumor suppressor that functions as an independent checkpoint for β-catenin transcriptional activity. Inactivation of Sox7 could promote the development of a majority of colorectal tumors and approximately half of prostate tumors. (Mol Cancer Res 2008;6(9):1421–10)

Expression of e-cadherin in high-risk breast cancer

Purpose E-cadherin expression is diverse, and differences in patient characteristics may produce variability in expression. Whereas some studies have indicated that downregulation of e-cadherin, associated with loss of cellular adhesiveness, was correlative with poor prognosis and metastasis, other studies have failed to confirm this. The present study uses a highly homogenous population of patients at high-risk for breast cancer, on the basis of ethnic and socio-economic status, to examine the relationship between e-cadherin and other prognostic markers in breast cancer.Methods Immunohistochemical staining was undertaken for estrogen (ER) and progesterone (PR) receptors, epidermal growth factor receptor 2 (Her-2), p53, vascular endothelial factor (VEGF), and hypoxia inducible factor 1α (HIF-1α) and the levels of these markers was compared to e-cadherin expression in a high-risk African-American patient population.Results E-cadherin expression persisted into the later stagers of the disease, and was strongly associated with Her-2 and HIF-1α expression, but not p53, ER/PR or VEGF.Conclusions In contrast to other studies on heterogeneous populations, e-cadherin is preserved in aggressive tumors in this high-risk population. The ethnic and socio-economic risk stratification needs to be accounted for in studies correlating markers and prognosis.

The Negative Predicative Value of Breast Fine-Needle Aspiration Biopsy: The Massachusetts General Hospital Experience

Abstract:  Breast fine‐needle aspiration biopsy (FNAB) has been increasingly accepted as an important triage tool for the evaluation of breast lumps. We examined the clinical utility and diagnostic accuracy of a negative breast FNAB result by studying 450 breast aspirates in 413 patients (average age 45 years) with a “negative” or benign cytologic interpretation performed at Massachusetts General Hospital over a 4‐year period. Of these patients, 121 (29%) underwent subsequent biopsy and 17 (4%) were found to have malignancy (3% of total negative FNABs; 14% with histology). None of these 17 patients had a triple negative test. A cohort of 115 patients had documentation of negative physical, radiologic, and cytologic examinations (the triple negative), none of whom were found to have malignancy on histologic or at least 2‐year clinical follow‐up (negative predictive value [NPV] = 100% with a triple‐negative test). Outside of the triple‐negative test, the NPV of a negative breast FNAB is reduced with a false‐negative rate of 7%. However, in the setting of a triple‐negative test, the NPV in our patient population was 100%, reassuring the patient and clinician that clinical follow‐up and not surgical intervention was sufficient for proper patient care. 

Correlation and expression of p53, HER-2, vascular endothelial growth factor (VEGF), and e-cadherin in a high-risk breast-cancer population.

BackgroundMany genetic traits common to aggressive breast carcinoma have been identified; yet little is known about the interrelationships of such traits during tumor development, especially in women prone to aggressive cancer. This study examined the expression of four biological markers associated with poor prognosis at each stage of breast cancer progression in primary tumors from women of lower economic status and assessed the relationship between these markers.MethodsArchived primary breast tumors from 77 patients were assessed by immunohistochemical analysis for expression of human epidermal growth receptor 2 (HER-2), p53, vascular endothelial growth factor (VEGF), and e-cadherin, and the relationships between the expressions of these molecules were studied.ResultsTwenty-two (29%) patients had advanced (stage III or IV) disease. HER-2, VEGF, e-cadherin, and p53 signal were positive for 31 (40%), 58 (75%), 63 (82%), and 37 (48%) of patients, respectively. Among the markers tested, only p53 exhibited a significant association between expression and stage of the disease (P = 0.012). Expression of e-cadherin was positively associated with HER-2 overexpression (P = 0.004), and high levels of HER-2 occurred with strongly positive e-cadherin tumors. Marginally significant positive associations were observed between HER-2 and p53 signal (P = 0.06), and between disease stage and e-cadherin expression (P = 0.08).ConclusionThe significant tendency toward expression of e-cadherin in conjunction with HER-2 overexpression in breast cancer is a novel finding. The association of p53 with more advanced stages of cancer emphasizes it as a key participant in metastatic processes in breast cancer.

Primary Small Bowel Carcinoid Tumor With Bilateral Breast Metastases: Report of 2 Cases With Different Clinical Presentations

CONTEXT Carcinoid tumor metastatic to the breast is uncommon and can closely mimic a mammary carcinoma. The differentiation of metastatic carcinoid tumor from primary breast tumor is important, however, owing to different clinical management and prognosis. OBJECTIVE The purpose of this study was to describe 2 patients with bilateral metastatic carcinoid tumors to the breast with different clinical manifestations. DESIGN We examined the radiological, clinical, cytologic, histologic, immunohistochemical, and ultrastructural features of these 2 cases. RESULTS In case 1, the tumor presented initially as a stellate mass on mammogram and was diagnosed as grade II infiltrating ductal carcinoma. It was only after the discovery of small intestinal, liver, ovarian, and contralateral breast masses, as well as careful morphologic and immunohistochemical evaluations, that the true nature of the tumor was realized. In case 2, the tumor initially presented as a small intestinal tumor with liver metastases and bilateral breast masses. The breast masses were diagnosed accurately as metastatic carcinoid tumor by morphologic and immunohistochemical evaluations. CONCLUSIONS Metastatic carcinoid tumor to the breast is uncommon, but poses a diagnostic challenge in that morphologically it can closely mimic a primary breast tumor. Careful attention to clinical features and the use of auxiliary immunohistochemical studies can help in arriving at the correct diagnosis.

Quantum Dots for Multiplexed Molecular Profiling of Cancer Cells and Tissue Specimens

Panels of cancer biomarkers are profiled by multiplexing conjugated quantum dots on cancer cells and clinical tissue specimens. This technique will allow an unprecedented understanding of molecular details of tumors with a subcellular resolution.

Biopsy Interpretation of the Kidney and Adrenal Gland (Biopsy Interpretation Series)

Well, someone can decide by themselves what they want to do and need to do but sometimes, that kind of person will need some biopsy interpretation of the kidney adrenal gland biopsy interpretation series references. People with open minded will always try to seek for the new things and information from many sources. On the contrary, people with closed mind will always think that they can do it by their principals. So, what kind of person are you?