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Biomedical subjects

William G Cance

Publications and source records attributed to William G Cance.

At least 19 recordsLinked to original sources
PubMed2006

Emerging implications of nanotechnology on cancer diagnostics and therapeutics.

Nanotechnology is multidisciplinary field that involves the design and engineering of objects <500 nanometers (nm) in size. The National Cancer Institute has recognized that nanotechnology offers an extraordinary, paradigm-changing opportunity to make significant advances in cancer diagnosis and treatment. In the last several decades, nanotechnology has been studied and developed primarily for use in novel drug-delivery systems (e.g. liposomes, gelatin nanoparticles, micelles). A recent explosion in engineering and technology has led to 1) the development of many new nanoscale platforms, including quantum dots, nanoshells, gold nanoparticles, paramagnetic nanoparticles, and carbon nanotubes, and 2) improvements in traditional, lipid-based nanoscale platforms. The emerging implications of these platforms for advances in cancer diagnostics and therapeutics form the basis of this review. A widespread understanding of these new technologies is important, because they currently are being integrated into the clinical practice of oncology.

Animals↗
PubMed2006

Vascular endothelial growth factor receptor-3 and focal adhesion kinase bind and suppress apoptosis in breast cancer cells.

Focal adhesion kinase (FAK) and vascular endothelial growth factor receptor-3 (VEGFR-3) are protein tyrosine kinases that are overexpressed in human cancer and play an important role in survival signaling. In addition to its involvement with cell survival, VEGFR-3 is a primary factor in lymphatic angiogenesis. Because FAK function is regulated by its COOH terminus (FAK-CD), we used FAK-CD as a target to identify binding partners. We isolated a peptide from a phage library that bound to FAK-CD, specifically the focal adhesion targeting domain of FAK and was homologous to VEGFR-3, suggesting these two tyrosine kinases physically interact. We have also shown that VEGFR-3 is overexpressed in human breast tumors and cancer cell lines. For the first time, we have shown the physical association of FAK and VEGFR-3. The association between the NH(2) terminus of VEGFR-3, containing the peptide identified by phage display, and the COOH terminus of FAK was detected by in vitro and in vivo binding studies. We then coupled a 12-amino-acid VEGFR-3 peptide, AV3, to a TAT cellular penetration sequence and showed that AV3 and not control-scrambled peptide caused specific displacement of FAK from the focal adhesions and affected colocalization of FAK and VEGFR-3. In addition, AV3 peptide decreased proliferation and caused cell detachment and apoptosis in breast cancer cell lines but not in normal breast cells. Thus, the FAK/VEGFR-3 interaction may have a potential use to develop novel molecular therapeutics to target the signaling between FAK and VEGFR-3 in human tumors.

Animals↗
PubMed2006

Successful minimally invasive parathyroidectomy for primary hyperparathyroidism without using intraoperative parathyroid hormone assays.

BACKGROUND: The need for intraoperative parathyroid hormone (iPTH) assays in minimally invasive parathyroidectomy (MIP) remains controversial. We report the results of MIP performed without the use of iPTH assays. METHODS: This was a single-institution retrospective review of patients with primary hyperparathyroidism treated with MIP between October 1, 1998, and December 31, 2002. RESULTS: Seventy-seven patients were studied. The mean preoperative calcium level was 11.4 mg/dL. All patients had a normal calcium level postoperatively (range, 7.4-10.2 mg/dL, mean, 9.1 mg/dL). Three patients (4%) required re-exploration for various reasons including the development of a second adenoma, secondary hyperparathyroidism, and discordant pathology. All 3 patients initially were eucalcemic. CONCLUSIONS: Our success rate of 96% using a combination of preoperative sestamibi scans, intraoperative gamma probe localization, and selective frozen pathology is consistent with the published success rates using iPTH assays of 95% to 100%. We conclude that MIP can be performed successfully without using iPTH assays.

Adolescent↗
PubMed2006

Preemptive surgery.

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Adenomatous Polyposis Coli↗
PubMed2006

Presentation and management of gastrointestinal stromal tumors of the duodenum.

Duodenal gastrointestinal stromal tumors (GIST) have been described primarily in isolated case reports. In order to learn more about duodenal GIST, a retrospective review of patients with GIST managed at a single institution between 2000 and 2005 was conducted. Thirty-eight GIST of the stomach and small bowel were analyzed. Eight (21%) were duodenal GIST. The median size of duodenal GIST (6.0 cm) and small bowel GIST (6.3 cm) was larger than the median size of gastric GIST (3.0 cm). The most common presentation of duodenal GIST was bleeding (50%) which was similar to other small bowel GIST (49%) but different from gastric GIST which were most commonly an incidental finding (62%). Two patients (25%) with duodenal GIST had a history of neurofibromatosis. The duodenal GIST were located in the 2nd (n = 5, 63%) and 3rd portion of duodenum (n = 3, 37%). Seven of 8 patients underwent complete resection of duodenal GIST. Pancreaticoduodenectomy was the most common operation performed (n = 5); 2 patients were treated with partial duodenal resection. No patients undergoing pancreaticoduodenectomy (n = 5) were found to have lymph node metastases. No patients received neo-adjuvant or adjuvant therapy with Imatinib. Following resection, 2 patients have recurred (12 and 48 mo.), 4 patients are without disease (1, 6, 6, and 24 mo.), 1 patient died postoperatively. Duodenal GIST are relatively rare tumors that present most commonly with gastrointestinal bleeding. Duodenal GIST are associated with neurofibromatosis. Many duodenal GIST require pancreaticoduodenectomy for complete removal.

Adult↗
PubMed2005

Retroperitoneal soft tissue sarcoma.

The objective of the current study was to define the optimal treatment for patients with retroperitoneal soft tissue sarcomas (RPS). The authors conducted a review of the pertinent literature and found that the majority of patients had locally advanced RPS at the time of diagnosis. Surgery was the mainstay of treatment, and macroscopic total excision was feasible in approximately 50-67% of patients. The 5-year probability of local control was approximately 50%, and the likelihood of developing distant metastasis was approximately 20-30%. The 5-year survival rate was approximately 50%, and deaths due to recurrent RPS continued to occur after 5 years. Postoperative radiotherapy (RT) decreased the likelihood of local recurrence, although it demonstrated no impact on survival. Adjuvant chemotherapy had no proven efficacy. The factor that was found to have the greatest impact on the prognosis for patients with RPS was the ability to achieve a macroscopic total resection. The authors concluded that RPS usually is advanced at the time of diagnosis. The optimal treatment was complete resection. Most patients experienced recurrent disease after surgery, and the most common site of failure was local. Adjuvant RT reduced the risk of local recurrence, but its impact on survival was questionable.

Adolescent↗
PubMed2005

Direct interaction of the N-terminal domain of focal adhesion kinase with the N-terminal transactivation domain of p53.

Focal adhesion kinase (FAK) is a nonreceptor kinase that is overexpressed in many types of tumors and associates with multiple cell surface receptors and intracellular signaling proteins through which it can play an important role in survival signaling. A link between FAK and p53 in survival signaling has been reported, although the molecular basis of these events has not been described. In the present study, we report that FAK physically and specifically interacts with p53 as demonstrated by pull-down, immunoprecipitation, and co-localization analyses. Using different constructs of N-terminal, central, and C-terminal fragments of FAK and p53 proteins, we determined that the N-terminal fragment of FAK directly interacts with the N-terminal transactivation domain of p53. Inhibition of p53 with small interfering p53 RNA resulted in a decreased complex of FAK and p53 proteins in 293 cells, and induction of p53 with doxorubicin in normal human fibroblasts caused an increase of FAK and p53 interaction. Introduction of the FAK plasmid into p53-null SAOS-2 cells was able to rescue these cells from apoptosis induced by expression of wild type p53. In HCT 116 colon cancer cells, co-transfection of FAK plasmid with p21, MDM-2, and BAX luciferase plasmids resulted in significant inhibition of p53-responsive luciferase activities, demonstrating that FAK can reduce transcriptional activity of p53. The results of the FAK and p53 interaction study strongly support the conclusion that FAK can suppress p53-mediated apoptosis and inhibit transcriptional activity of p53. This provides a novel mechanism for FAK-p53-mediated survival/apoptotic signaling.

Apoptosis↗
PubMed2005

Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines.

Inhibition of focal adhesion kinase (FAK), a non-receptor tyrosine kinase linked to tumour cell survival, causes cell rounding, loss of adhesion and apoptosis in human cancer cell lines. In this study, we tested antisense oligonucleotide inhibitors of FAK, in combination with 5-fluorouracil (5-FU), to increase its sensitivity in human melanoma cell lines. Antisense oligonucleotides directed to the 5' mRNA sequence of FAK and missense control oligonucleotides were used. In BL melanoma cells, treatment with FAK antisense oligonucleotide was associated with a 2.5-fold increase in cell death compared with treatment with control oligonucleotide (33+/-2% vs. 13+/-3%, P<0.0001). 5-FU alone had no effect on BL cells (4.4% cell death, P=0.15). The addition of 5-FU after antisense oligonucleotide resulted in a significant synergistic increase in cell death equal to 69+/-2% compared with treatments with antisense oligonucleotide alone, 5-FU alone and control oligonucleotide (P<0.0001). Similar results were found in the C8161 melanoma cell line. In both cell lines, reduction in cell viability was accompanied by an increased loss of adhesion and increased apoptosis that was proportional to the decrease in viability. Treatment with antisense oligonucleotide plus 5-FU resulted in significantly decreased p125FAK expression in both C8161 and BL melanoma cell lines, demonstrated by Western blot analyses. These data show that the downregulation of FAK by antisense oligonucleotide combined with 5-FU chemotherapy results in a greater loss of adhesion and greater apoptosis in melanoma cells than treatment with either agent alone, suggesting that the combination may be a potential therapeutic agent for human melanoma in vivo.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Adjuvant postoperative radiotherapy for colon carcinoma.

BACKGROUND: The objective of this report was to review the role of adjuvant postoperative radiotherapy (RT) for patients with adenocarcinoma of the colon. METHODS: The authors reviewed the pertinent literature. RESULTS: Data suggested that locoregional postoperative RT improves both local control and survival for patients with T4N0-N1 tumors. There also may be a benefit for patients with T3N1-N2 tumors, but the data were equivocal. Whole abdominal RT may result in a similar benefit but is associated with increased toxicity. CONCLUSIONS: Postoperative RT should be considered for patients with T4N0-N1 colon carcinoma. Locoregional fields should be used.

Adenocarcinoma↗
PubMed2004

Activated Src increases adhesion, survival and alpha2-integrin expression in human breast cancer cells.

Focal adhesion kinase (FAK) is an intracellular kinase that localizes to focal adhesions. FAK is overexpressed in human tumours, and FAK regulates both cellular adhesion and anti-apoptotic survival signalling. Disruption of FAK function by overexpression of the FAK C-terminal domain [FAK-CD, analogous to the FRNK (FAK-related non-kinase) protein] leads to loss of adhesion and apoptosis in tumour cells. We have shown that overexpression of an activated form of the Src tyrosine kinase suppressed the loss of adhesion induced by dominant-negative; adenoviral FAK-CD and decreased the apoptotic response in BT474 and MCF-7 breast cancer cell lines. This adhesion-dependent apoptosis was increased by the Src-family kinase inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine]. We have also shown that expression of activated Src in breast cancer cells increased the expression of alpha2-integrin and that overexpression of alpha2-integrin suppressed FAK-CD-mediated loss of adhesion. Our results suggest a model in which Src regulates adhesion and survival through enhanced expression of the alpha2-integrin. This provides a mechanism through which Src promotes cellular adhesion and alters the adhesive function of FAK.

Apoptosis↗
PubMed2004

Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis.

Focal adhesion kinase (FAK) is a protein tyrosine kinase that is overexpressed in a subset of invasive breast cancers. FAK transmits signals that mediate several functions including tumor cell proliferation, migration, adhesion and survival. We used immunohistochemical techniques to assess FAK expression in patients with fibrocystic disease (FCD), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC). Formalin-fixed, paraffin-embedded (FFPE) tissue sections were obtained from 119 patients (12 FCD, 38 ADH, 51 DCIS and 18 IDC). The anti-FAK 4.47 monoclonal antibody was used to detect FAK expression. FAK expression was scored as high (3 or 4 intensity and > or =90% positive cells) or low. The DCIS tissue sections demonstrated high FAK expression in 34/51 (66%) of the sections. High FAK expression was demonstrated in 6/18 (33%) of the IDC tissue sections and 8/38 (21%) of the ADH tissue sections. None (0/12) of the FCD tissues sections stained high for FAK. The pattern of FAK expression in DCIS was significantly higher than ADH (p < 0.0001) and IDC (p = 0.02). We conclude that FAK overexpression in preinvasive, DCIS tumors precedes tumor cell invasion or metastasis, suggesting that FAK may function as a survival signal and be an early event in breast tumorigenesis.

Breast Diseases↗
PubMed2004

Focal adhesion kinase overexpression in endometrial neoplasia.

Focal adhesion kinase (FAK) is a protein tyrosine kinase that is a critical mediator of signaling events between cells and their extracellular matrix. Elevations in FAK mRNA and protein overexpression have been linked to tumor cell capacity for invasion and metastasis. FAK expression has been shown to be elevated in a variety of solid tumors. The purpose of this study was to evaluate for FAK upregulation in endometrial neoplasia. Tissue microarray blocks were made from formalin-fixed, paraffin-embedded archival tissue, including 115 carcinoma (100 endometrioid, 10 serous, and 5 clear cell), 28 hyperplasia, and 38 normal specimens using 1-mm punches. The tissue was immunostained with monoclonal antibody for FAK and p53. Immunoreactivity was scored by intensity (0-4+ scale) and percent positive staining. FAK overexpression was categorized as 4+ cytoplasmic intensity in more than 90% of neoplastic cells. Positive p53 was categorized at least 2+ nuclear intensity in more than 10% of neoplastic cells. Higher rates of FAK upregulation were identified in endometrial hyperplasia (P = 0.025) and carcinoma (P < 0.001) versus normal endometrium. FAK overexpression in carcinoma correlated with higher FIGO grade (P = 0.025) and p53 overexpression (P < 0.001). FAK was consistently overexpressed in high-grade tumors regardless of subtype, including 8 of 10 serous tumors, 4 of 5 clear cell tumors, and 16 of 23 grade 3 endometrioid tumors. In conclusion, upregulation of FAK is seen in both endometrial hyperplasia and carcinoma, implying that FAK may play an important role in endometrial carcinogenesis. FAK overexpression in endometrial carcinoma correlates with higher FIGO grade and p53 overexpression.

Carcinoma, Endometrioid↗
PubMed2004

Focal adhesion kinase suppresses apoptosis by binding to the death domain of receptor-interacting protein.

Tumor cells resist the apoptotic stimuli associated with invasion and metastasis by activating survival signals that suppress apoptosis. Focal adhesion kinase (FAK), a tyrosine kinase that is overexpressed in a variety of human tumors, mediates one of these survival signals. Attenuation of FAK expression in tumor cells results in apoptosis that is mediated by caspase 8- and FADD-dependent pathways, suggesting that death receptor pathways are involved in the process. Here, we report a functional link between FAK and death receptors. We have demonstrated that FAK binds to the death domain kinase receptor-interacting protein (RIP). RIP is a major component of the death receptor complex and has been shown to interact with Fas and tumor necrosis factor receptor 1 through its binding to adapter proteins. We have shown that RIP provides proapoptotic signals that are suppressed by its binding to FAK. We thus propose that FAK overexpression in human tumors provides a survival signal function by binding to RIP and inhibiting its interaction with the death receptor complex.

Animals↗
PubMed2004

Neoadjuvant chemotherapy of breast cancer.

The use of neoadjuvant chemotherapy in the treatment of breast cancer has been evolving during the past two decades. Fisher's group accomplished the scientific rationale in mouse models in the 1970s. The Milan group was the first to use neoadjuvant therapy in locally advanced breast cancer and also determined that adjuvant sequential doxorubicin with cyclophosphamide/methotrexate/fluorouracil (CMF) offered improved survival when compared to alternating CMF with doxorubicin. Other groups (M. D. Anderson and NSABP) have evaluated similar doxorubicin-based neoadjuvant therapies in locally advanced breast cancer (LABC) and in early disease. These studies have shown an increase in breast-conserving therapy (BCT) and an increase in pathologic complete response (pCR) when neoadjuvant therapy was used. Due to anthracycline resistance, taxanes were added to the doxorubicin-based neoadjuvant chemotherapy regimen with an increase in BCT and pCR than when an anthracycline regimen was used alone. Overall survival has yet to be determined when comparing an anthracycline-based regimen to the same regimen with the addition of a sequential taxane. Therefore, a combined treatment of an anthracycline/cyclophosphamide/taxane regimen is the recommended neoadjuvant chemotherapy for patients with breast cancer.

Animals↗
PubMed2003

Focal adhesion kinase N-terminus in breast carcinoma cells induces rounding, detachment and apoptosis.

Focal adhesion kinase (FAK) has a central role in adhesion-mediated cell signalling. The N-terminus of FAK is thought to function as a docking site for a number of proteins, including the Src-family tyrosine kinases. In the present study, we disrupted FAK signalling by expressing the N-terminal domain of FAK (FAK-NT) in human breast carcinoma cells, BT474 and MCF-7 lines, and non-malignant epithelial cells, MCF-10A line. Expression of FAK-NT led to rounding, detachment and apoptosis in human breast cancer cells. Apoptosis was accompanied by dephosphorylation of FAK Tyr(397), degradation of the endogenous FAK protein and activation of caspase-3. Over-expression of FAK rescued FAK-NT-mediated cellular rounding. Expression of FAK-NT in non-malignant breast epithelial cells did not lead to rounding, loss of FAK phosphorylation or apoptosis. Thus FAK-NT contributes to cellular adhesion and survival pathways in breast cancer cells which are not required for survival in non-malignant breast epithelial cells.

Apoptosis↗
PubMed2003

Breast cancer cell line proliferation blocked by the Src-related Rak tyrosine kinase.

Rak is a 54 kDa protein tyrosine kinase originally isolated from breast cancer cells and expressed in epithelial cells. It resembles the protooncogene Src structurally but lacks an amino-terminal myristylation site and localizes to the nuclear and perinuclear regions of the cell. We report here that expression of Rak in 2 different breast cancer cell lines inhibits growth and causes G(1) arrest of the cell cycle. This growth inhibition is kinase-dependent but does not require the Rak SH2 or SH3 domain. Rak also binds to the pRb tumor-suppressor protein but inhibits growth even in cells that lack pRb. These results suggest that Rak regulates cell growth by phosphorylating perinuclear proteins and has a function that is distinct from the Src-related kinase family.

Blotting, Western↗
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↗