Biomedical subjects

William G Cance

Publications and source records attributed to William G Cance.

25 records · Page 2Linked to original sources

PubMed2003

The C-terminal domain of focal adhesion kinase reduces the tumor cell invasiveness in chondrosarcoma cell lines.

Human chondrosarcoma is a malignancy that has no effective systemic therapy, making the interruption of the metastatic cascade critical to enhance patient survival. The processes of local invasion and metastases share similar mechanisms at a cellular level. Focal adhesion kinase (FAK) has been implicated in local invasion of malignant tumor cells. In the current manuscript we examine the effect of FAK inhibition on cell attachment to extracellular matrix (ECM) and in vitro invasion. Bovine articular chondrocytes and two human chondrosarcoma cell lines were utilized to examine FAK activity in tumor cell invasiveness. Endogenous FAK activity was inhibited by adenoviral transfection with the C-terminal domain of FAK. This inhibition resulted from decreased FAK phosphorylation, while FAK expression remained unchanged. Inhibition of FAK phosphorylation and hence its activity lead to decreased cell adhesion to Type II collagen and decreased cell invasiveness. These effects were not due to changes in integrin expression, indicating that the inhibition was the result of disruption of outside: in signaling. There are three important aspects to these results. The first is that interruption of transmembrane signaling can affect cell attachment. The second is that in chondrosarcoma, cell differentiation correlates with FAK expression and metastatic potential. Thirdly, that cell invasiveness correlates with FAK activity and implies a mechanistic role for this molecular complex in local invasion and metastasis.

Animals↗

PubMed2003

A decade of tyrosine kinases: from gene discovery to therapeutics.

Tyrosine kinases are key regulators of breast cancer cell survival and proliferation. Ten years ago, we conducted a screen for protein kinases expressed in primary human breast tumors and cultured cancer cells. Here, we review the progress from the last ten years in understanding the functions of these kinases with a focus on breast cancer. Three themes emerge: (1). tyrosine kinases regulate proliferation through the MAP Kinase pathway, (2). tyrosine kinases regulate cellular survival through the PI3 Kinase-Akt pathway, and (3). the cell cycle is regulated through a complex series of serine-threonine kinases. Our improved understanding of these signaling cascades has led to novel strategies for therapeutic intervention in breast cancer.

Apoptosis↗

PubMed2003

Extracapsular extension of the sentinel lymph node metastasis: a predictor of nonsentinel node tumor burden.

OBJECTIVE: To identify predictors of nonsentinel node (NSN) tumor involvement in patients with a tumor-involved sentinel node (SN). SUMMARY BACKGROUND DATA: For many breast cancer patients who undergo intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL), the SN is the only tumor-involved axillary node. Associations between NSN tumor involvement and several clinical and histopathologic factors have been identified. The authors hypothesize that extracapsular extension (ECE) of the SN metastasis is highly predictive of NSN tumor involvement. METHODS: Between May 1998 and December 2001, 260 patients (263 cases) with clinical T1 or T2 (<5.0 cm) breast cancer underwent LM/SL at the University of North Carolina, using a combined blue dye and technetium sulfur colloid technique. In all cases with a tumor-involved SN, axillary lymph node dissection (ALND) was recommended. Statistical analysis, with Pearson chi-square tests, Fisher exact test, and multiple logistic regression, was performed. RESULTS: The SN contained tumor in 74 (28.1%) cases. ALND was performed in 70 of the 74 cases. ECE of the SN metastasis was present in 18 (25.7%) of the 70 cases. Patients with ECE of the SN metastasis were more likely to have NSN tumor involvement and had a greater total number of tumor-involved nodes than patients without ECE of the SN metastasis. Increasing size of the SN metastasis and increasing size of the primary tumor, examined as continuous variables, were associated with an increased likelihood of NSN tumor involvement on univariate analysis. However, only ECE of the SN metastasis was associated with NSN tumor involvement on multivariate analysis. CONCLUSIONS: ECE of the SN metastasis is a strong predictor of NSN tumor involvement. All patients with ECE of the SN metastasis should undergo mandatory completion ALND.

Adult↗

PubMed2003

Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases: immunohistochemistry and real-time PCR analyses.

PURPOSE: Focal adhesion kinase (FAK), a protein tyrosine kinase that functions in signaling events between cells and their extracellular matrix, is overexpressed in a variety of human solid tumors. To determine whether FAK expression is up-regulated in colorectal cancer, we analyzed FAK mRNA and protein levels in primary colorectal tumors and colorectal liver metastases. EXPERIMENTAL DESIGN: p125(FAK) expression in formalin-fixed paraffin-embedded (FFPE) tissue was studied using immunohistochemical assays on 24 matched primary colorectal carcinomas and colorectal liver metastases as well as 18 different colorectal liver metastases using monoclonal anti-FAK 4.47. FAK mRNA expression was quantitated by real-time PCR on 39 matched normal colorectal mucosa and primary colorectal carcinomas as well as on 17 separate liver metastases. RESULTS: Elevated levels of p125(FAK) expression were demonstrated in both primary colorectal tumors and colorectal liver metastases compared with normal colorectal mucosa. Immunohistochemistry experiments demonstrated equivalent FAK expression in matched samples of colorectal primary tumors and liver metastases. Using real-time PCR in 39 matched samples, FAK mRNA copy number was significantly higher in primary colorectal tumors compared with normal colorectal mucosa. FAK expression was analyzed by both real-time PCR and immunohistochemistry in a separate set of colorectal liver metastases. Immunohistochemistry demonstrated high levels of FAK expression in 89% of samples. Furthermore, FAK mRNA copies in these unmatched liver metastases were significantly higher than the primary tumor FAK mRNA copies. CONCLUSION: These experiments have shown that both primary colorectal cancers and colorectal liver metastases express high levels of FAK mRNA and p125(FAK) protein. Furthermore, the majority of colorectal liver metastases demonstrated robust FAK expression equivalent to or greater than that in the primary colorectal tumor.

Blotting, Western↗

PubMed2003

Simultaneous inhibition of focal adhesion kinase and SRC enhances detachment and apoptosis in colon cancer cell lines.

Focal adhesion kinase (FAK) and Src have been shown to be overexpressed in colon cancer. We have studied the role of these two kinases in resistance to apoptosis. Adenovirus-containing FAK-CD (Ad-FAK-CD), a dominant-negative, COOH-terminal portion of FAK, was used to inhibit FAK and cause apoptosis. Colon cancer cell lines were more resistant to Ad-FAK-CD-induced detachment and apoptosis than the breast cancer cell line, BT474. Colon cancer cell lines overexpressed highly active Src and FAK. Ad-FAK-CD-induced apoptosis was significantly increased by PP2, an inhibitor of Src family kinases. Activation of caspase-3, down-regulation of FAK, and Src and AKT activities were demonstrated in Ad-FAK-CD + PP2-treated colon cancer cells undergoing apoptosis. The results suggest that FAK and Src are both important survival factors, playing a role in protecting colon cancer cell lines from Ad-FAK-CD-induced apoptosis. Dual inhibition of these kinases may be important for therapies designed to enhance the apoptosis in colon cancers.

Adenoviridae↗

PubMed2002

Long-term outcome of neoadjuvant therapy for locally advanced breast carcinoma: effective clinical downstaging allows breast preservation and predicts outstanding local control and survival.

OBJECTIVE: To review the long-term follow-up data from the authors' institutional experience of 62 patients with locally advanced breast cancer (LABC) treated with a uniform multimodality regimen. The authors determined the rate of breast preservation, the disease-free and overall survival, and the factors associated with locoregional and distant recurrent disease. SUMMARY BACKGROUND DATA: It remains a challenge to achieve local and distant control of LABC. Over the last decade, preoperative or neoadjuvant chemotherapy has emerged as the standard of care for these patients. Successful tumor downstaging has been associated with increased rates of breast-conserving therapy (BCT), but the overall effect on long-term survival remains to be seen. METHODS: This study examines a cohort of 62 patients with LABC treated at the authors' institution from 1992 to 1998. The uniform treatment regimen consisted of neoadjuvant doxorubicin (Adriamycin), followed by operation (BCT if sufficient clinical downstaging), followed by non-cross-resistant cyclophosphamide/methotrexate/5-fluorouracil, followed by radiation therapy. Treatment was both dose-intensive and time-intensive, with a total treatment time of 32 to 35 weeks. RESULTS: In this patient population, the median age was 44 years, with approximately two thirds white patients and one third African American. Eighty-two percent of patients were clinical stage III at presentation, 13 patients had T4d inflammatory cancers, and 3 patients were stage IV at diagnosis. Eighty-four percent of patients demonstrated a significant clinical response to doxorubicin. Twenty-eight patients had sufficient clinical downstaging to attempt BCT, and 22 (45%) of 49 noninflammatory patients underwent successful BCT. Pathologic complete response was seen in 15% of patients. Median follow-up for the cohort was 70 months. The local recurrence rate was 14%, including two ipsilateral breast tumor recurrences (10%) in the BCT patients. Seven (12%) patients developed a new primary cancer in the contralateral breast. Distant metastases occurred in 18 (31%) patients, and the 5-year overall survival rate for the cohort was 76%. Furthermore, in the patients who underwent an attempt at BCT, the survival rate was 96% at 5 years. CONCLUSIONS: Dose-intensive and time-intensive multimodality neoadjuvant therapy was successfully administered to a mixed racial group over shortened times. Patients who had sufficient clinical downstaging to allow BCT have the best long-term outcome. Patients who required mastectomy are at a higher risk of relapse, as well as the development of new contralateral cancers, yet have 5-year survival rates of over 50%.

Adult↗

PubMedDate not supplied

Overexpression of the receptor tyrosine kinase Tie-1 intracellular domain in breast cancer.

OBJECTIVE: Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie-1) is a receptor tyrosine kinase that regulates angiogenesis and antiapoptotic survival signaling. Tie-1 expression is generally associated with endothelial cells and neovascularization. We previously identified Tie-1 in human breast tumor samples using a PCR-based screen for protein kinases expressed in breast tumors. The purpose of this study was to determine the cell types expressing Tie-1, whether Tie-1 is expressed in tumor cells, and to examine the regulation of Tie-1 in breast cancer. METHODS: Tie-1 expression was analyzed by Western blot and immunohistochemistry using an antibody to the carboxy terminus of Tie-1. Tie-1 expression was determined in a variety of cancer cell lines, clinical breast and colon tumor samples, and in corresponding benign tissue from the same patient. Tie-1 expression and distribution in breast tumors was scored by immunohistochemistry. RESULTS: Tie-1 was overexpressed in 14/23 breast tumors compared with 0/9 corresponding normal tissues from the same patients. Immunohistochemistry revealed that Tie-1 was overexpressed in epithelial breast cancer cells and ductal carcinoma in situ. In all breast tumor samples, Tie-1 was expressed as a truncated 40- to 43-kD doublet consisting of the intracellular portion of the protein, which contains the tyrosine kinase catalytic domain. The 40- to 43-kD Tie-1 doublet was expressed in a broad variety of cell lines. CONCLUSIONS: We have shown that breast cancer cells overexpress a cleaved form of the Tie-1 protein. Our results implicate the intracellular domain of Tie-1, which includes the catalytic kinase domain, in breast cancer progression.

Biomarkers, Tumor↗