Jia-Lin Yang

STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (Review)

Signal transducer and activator of transcription 3 (STAT3) regulates many critical functions in human normal and malignant tissues, such as differentiation, proliferation, survival, angiogenesis and immune function. Constitutive activation of STAT3 is implicated in a wide range of human cancers. As such, STAT3 has been studied as a tumour therapeutic target. This review aimed principally to summarise the updated research on STAT3 inhibition studies and their therapeutic potential in solid tumours. Recent literature associated with STAT3 inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis. Constitutive activation of STAT3 has been identified as abnormal and oncogenic. The pathway of STAT3 activation and signal transduction identifies 3 approaches for inhibition: modulating upstream positive or negative regulators, regulating RNA (DN-STAT3, anti-sense RNA, siRNA and microRNA) or targeting STAT3 protein at different domains. The last approach using small molecule STAT3 inhibitors has been the most examined so far with both preclinical and clinical studies. Targeting STAT3 using a specific inhibitor may be a useful cancer treatment approach, with the potential for a broad clinical impact.

Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets

Urokinase‐type plasminogen activator (uPA) and its receptor (uPAR), plasminogen (Plg), and plasminogen activator inhibitors‐1 and ‐2 (PAI‐1 and PAI‐2) have been observed in many cancers and may contribute to progression and metastasis. In our study, we examined the expression of the 5 proteins by immunohistochemistry in 59 consecutive primary colorectal cancers (CRC) and correlated the protein expression with patient outcome. In addition, we determined the effect of down‐regulation of uPAR on the invasive/metastatic capability of CRC cells, by measuring antisense‐uPAR transfected HCT116 and control cell lines, in terms of uPAR expression, uPA‐binding activity, invasiveness through Matrigel in vitro and metastasis after cecal orthotopic implantation in nude mice in vivo. We found that higher expression of uPA or uPAR in primary tumor tissues was positively correlated with distant metastasis of CRC (Mann‐Whitney, p < 0.02) and negatively correlated with both patient overall survival (OS) and cancer‐specific survival (CSS; Cox model, p < 0.04). The prognostic value of uPA and uPAR for both OS and CSS was independent of other variables (multivariate Cox model, p < 0.007). Antisense‐uPAR transfected HCT116 cells, which expressed significantly lower levels of total cellular and cell surface uPAR proteins and uPA‐binding activity compared with either wild‐type or cells transfected with vector alone (Bonferroni, p < 0.05/3), consistently showed decreased invasiveness through Matrigel (Bonferroni, p < 0.05/3) and decreased metastasis formation in nude mice (Fisher, p < 0.05). Our data suggest that uPAR and uPA are independent prognostic factors in CRC; anti‐uPAR treatment, which affects both uPAR and uPA levels, may have potential for new treatment of the disease. Int. J. Cancer 89:431–439, 2000.

Anal fistula: Levovist®-enhanced endoanal ultrasound: A pilot study

AbstractPURPOSE: The aim of the study was to investigate the usefulness of the contrast agent Levovist® in ultrasound assessment of anal fistula. METHODS: Fifteen patients (11 females, mean age 46) with a diagnosis of anal fistula were assessed by physical examination, conventional ultrasound, Levovist®-enhanced ultrasound, and surgery. Levovist® was injected via a cannula into the fistula. The results of physical examination, conventional ultrasound and Levovist®-enhanced ultrasound were compared with surgical findings as criterion standard. RESULTS: At physical examination, three intersphincteric fistulas and two sinuses were diagnosed. Using conventional ultrasound, five intersphincteric and five transsphincteric fistulas were found; four fistulas and one sinus were not detected. Levovist®-enhanced ultrasound revealed one sinus, five intersphincteric, seven transsphincteric, and one extrasphincteric fistulas; only one fistula was not detected. At surgery, three intersphincteric, seven transsphincteric, and two sinuses were found; however, the extrasphincteric fistula detected by Levovist® was missed. Compared with physical examination, Levovist®-enhanced ultrasound and surgery were significantly favorable in the diagnosis of anal fistula (P < 0.05 in chi-squared test and Fisher’s exact probability test). The concordance rate of surgery with conventional ultrasound was 69 percent (9/13) and with Levovist®-enhanced ultrasound was 77 percent (10/13). However, because the extrasphincteric fistula was missed at surgery, the accuracy of Levovist®-enhanced ultrasound was in fact 85 percent (11/13) if surgical finding was not used as the standard. The internal opening was detected at physical examination in 2 patients (13 percent), with conventional ultrasound in 4 patients (27 percent), with Levovist®-enhanced ultrasound in 9 patients (60 percent) and during surgery in 11 patients (85 percent). Consistently, Levovist®-enhanced ultrasound and surgery were significantly better than physical examination in the diagnosis of internal opening (P < 0.05). One secondary extension and two sphincter defects were detected by both types of ultrasound. The extension was not confirmed during surgery. No patients developed recurrence or nonhealing of wound. One patient developed incontinence to flatus and one developed a perianal hematoma. CONCLUSION: Levovist®-enhanced ultrasound is better at assessing anal fistula than physical examination and conventional ultrasound. However, a future trial comparing Levovist®, hydrogen peroxide, and magnetic resonance imaging is needed to establish which is the most cost-effective preoperative imaging technique to use.

microRNA-34 family and treatment of cancers with mutant or wild-type p53 (Review)

In the last decade, microRNAs (miRNAs; small noncoding RNA molecules) as post-transcriptional regulators have been a hotspot in research for their involvement in biological processes and tumour development. However, there have been few reviews focusing on a single miRNA family. The dysregulation of miRNAs appears to play a crucial role in cancer pathogenesis where they exert their effect as oncogenes or as tumour suppressors. This review summarises current studies on the dysregulation of the microRNA-34 (miR-34) family in different types of cancers and its role in the p53 network. The structure of the miR-34 family members includes p53-binding sites reflecting their function as tumour suppressors downstream of the p53 pathway. miR-34 dysregulation occurs in cancers, including several epithelial cancers, melanomas, neuroblastomas, leukemias and sarcomas, in the presence or absence of the p53 mutation. For these cancers, functional restoration of miR-34 is a useful novel therapy. As evidenced from preclinical and clinical studies, the miR-34 family plays an important role in the treatment of miR-34-dysregulated cancers with mutant or wild-type p53. This review will have a potential impact in the clinical treatment of p53-mutant and/or miR-34-dysregulated cancers using a miR-34 restoration approach.

Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer

AbstractPurpose PTEN is an essential tumour suppressor gene which encodes a phosphatase protein that antagonises the PI3K/Akt/mTOR antiapoptotic pathway. Impairment of this tumour suppressor pathway potentially becomes a causal factor for development of malignancies. This review aims to assess current understanding of mechanisms of dysfunction involving the PI3K/PTEN/Akt/mTOR pathway linked to tumorigenesis and evaluate the evidence for targeted therapy directed at this signalling axis.MethodsRelevant articles in scientific databases were identified using a combination of search terms, including “malignancies”, “targeted therapy”, “PTEN”, and “combination therapy”. These databases included Medline, Embase, Cochrane Review, Pubmed, and Scopus.ResultsPI3K/PTEN expression is frequently deregulated in a majority of malignancies through genetic, epigenetic, and post-transcriptional modifications. This contributes to the upregulation of the PI3K/Akt/mTOR pathway which has been the focus of intense clinical studies. Targeted agents aimed at this pathway offer a novel treatment approach in a variety of haematologic malignancies and solid tumours. Compared to single-agent use, greater response rates were obtained in combination regimens, supporting further investigation of suitable drug combinations in a broad spectrum of malignancies.ConclusionActivation of the PI3K/PTEN/Akt/mTOR pathway is implicated both in the pathogenesis of malignancies and development of resistance to anticancer therapies. Therefore, PI3K/Akt/mTOR inhibitors are a promising therapeutic option, in association with systemic cytotoxic and biological therapies, to enable sustained clinical outcomes in cancer treatment. Therapeutic strategies could be tailored according to appropriate biomarkers and patient-specific mutation profiles to maximise benefit of combination therapies.

Preoperative Chemoradiotherapy (Modified Eilber Protocol) Provides Maximum Local Control and Minimal Morbidity in Patients With Soft Tissue Sarcoma

BackgroundLocal recurrence rates of 15% to 30% after treatment of soft tissue sarcoma (STS) are still common but unacceptable. Our hypothesis was that a refined neoadjuvant chemotherapy and radiation protocol (modified Eilber protocol) improves local control rates while minimizing major morbidity.MethodsConsecutive patients with STS deep to the fascia of the extremity or trunk during 1984 to 1996 were treated with 3 days of doxorubicin (30 mg/day) and sequential radiation (300 cGy/day for 10 days). Wide excision with limb preservation was performed 4 to 8 weeks after radiation completion. Treatment complications, margins, local recurrence, and survival were prospectively documented.ResultsOf 75 patients, 66% had tumors >5 cm, and 71% were grade 2/3. In eight patients, negative margins were not achieved, and four of these had amputation (95% limb salvage). Three of the remaining four had local recurrence with a 5- and 7-year actuarial local control rate of 50% and 25%, respectively. In contrast, of the 67 patients with negative margins, a local control rate of 97% at 5 years and 94% at 7 years and an overall survival of 63% were achieved. Although margin (P = .001) and stage (P = .035) were correlated, these were not significant on multivariate Cox regression analysis. Risk factors for death included tumor stage (hazard ratio, 1.54; P = .001) and tumor grade (hazard ratio, 1.4; P = .02). Three patients (4%) required reoperation for tissue loss, and eight patients (10.6%) developed minor wound complications.ConclusionsThis modified Eilber protocol seems to maximize local control and minimize major wound complications for extremity/truncal STS.

Higher expression of oncoproteins c-myc, c-erb B-2/neu, PCNA, and p53 in metastasizing colorectal cancer than in nonmetastasizing tumors.

AbstractBackground: Expression of individual oncogenes may predict outcome in patients with metastatic colorectal cancer (CRC). We studied the oncogene profile in the tumors of patients with CRC and assessed their value as predictors of liver metastases. Methods: The oncoproteins c-myc, c-erbB-2/neu (c-neu), PCNA and p53, were measured by immunohistochemistry in sections of metastasizing human CRC (n=34) and their liver secondaries as well as in sections of nonmetastasizing CRC (n=25). Results: The metastasizing primary CRC expressed proliferating-cell nuclear antigen (PCNA), c-neu, and c-myc at significantly higher levels than the nonmetastasizing primary cancer. p53 was also overexpressed in the metastatic group compared with the nonmetastasizing CRC, but this difference was not significant. The frequency of expression of all these markers was similar in the metastasizing primary CRC and the liver secondaries from the same patients. There was no correlation between the expression of the individual markers and histological grade, DNA ploidy, and subsequent local recurrence and lung metastasis and survival. However, when both groups were assessed together, positive expression of c-myc was more likely to occur in poorly differentiated tumors, whereas PCNA expression increased with more advanced Dukes stages. Conclusion: These results suggest that the overexpression of c-myc, c-neu, PCNA, and p53 may occur in CRC that are likely to metastasise to the liver.

Genetic Markers of Survival and Liver Recurrence after Resection of Liver Metastases from Colorectal Cancer

A significant number of patients with liver metastases from colorectal cancer (CRC) achieve 5-year survival after liver resection. Increased expression of genetic markers in the primary tumor are known to predict outcome after colonic resection, but the predictive value of such markers after resection of hepatic metastases is unknown. The objective of this study was to evaluate whether DNA content and multiple genetic markers, separately or expressed together, can predict patient outcome (liver recurrence and survival) after resection of hepatic metastases. We studied the paraffin-embedded liver tissue of 71 consecutive patients who had undergone a potentially curative resection of hepatic metastases from CRC. Using DNA flow cytometry and immunohistochemical staining techniques we determined the DNA content and the level of co-expression of seven tumor-associated proteins: proliferating cellular nuclear antigen (PCNA), epidermal growth factor receptor (EGFr), p53, c-erbB-2, H-ras, c-myc, and nm23. Three endpoints (liver recurrence, cancer specific, overall survival) were correlated with these tumor markers. The 5-year overall survival of the group was 31.2%. There was no correlation detected between the DNA aneuploidy and overall or cancer-specific survival. Similarly, expression of the individual tumor-associated proteins did not predict survival. Patients whose tumors co-expressed multiple markers had survivals similar to those whose tumors expressed fewer markers. However, a significant difference in hepatic recurrence was found between the p53-positive and p53-negative patients (p= 0.007), with marker-negative tumors having decreased recurrence. In conclusion, this study demonstrates that the DNA content and genetic markers c-myc, c-erbB-2, EGFr, H-ras, p53, PCNA, and nm23 do not predict survival after potentially curative resection of hepatic metastases from CRC. However, the immunoreactivity of p53 may be an important marker of local recurrence in the liver, which may be useful if re-resection of metastatic liver tumors is considered a viable management option in this disease.

Combined therapies for cancer: a review of EGFR-targeted monotherapy and combination treatment with other drugs.

Targeted therapy refers to anticancer treatment which specifically targets key molecules of cancer cells and/or neovascular cells, aiming to thus interfere with processes of tumorigenesis, cancer progression and metastasis. The epidermal growth factor receptor (EGFR) was the first receptor to be proposed for targeted cancer therapy, having been found to be commonly overexpressed in a range of solid tumors and play a role in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Despite successful development of EGFR-targeted pharmacological agents, clinical and molecular studies have indicated several limitations to the broad application of this treatment as a monotherapy. Novel combination treatments which might optimize the effect of EGFR inhibition have, therefore, been investigated. Research conducted into the mechanisms of action and synergy of these combination treatments is likely to enhance the role of the EGFR target in future cancer treatment.

Regulation of epidermal growth factor receptor in human colon cancer cell lines by interferon α

Background and aim: The biology of growth factor receptor expression has implications for receptor specific cancer therapy. In this study, we examined: (a) regulation of epidermal growth factor receptor (EGFR) expression in a panel of 10 human colon cancer cell lines using interferon α (IFN-α); (b) ability of IFN-α to inhibit cell proliferation; and (c) sensitivity of IFN-α pretreated cells to EGF. Methods: Cell proliferation was measured both by crystal violet colorimetric and clonogenic assays. Cell surface, intracellular, and/or total cell protein expression of EGFR was assessed by indirect immunofluorescence flow cytometry and/or fluorescein isothiocyanate (FITC)-EGF binding and internalisation flow cytometric assay. Results: IFN-α treatment upregulated expression of cell surface EGFR in seven of 10 colon cancer cell lines within 16 hours, reaching a peak within 48–96 hours; this was accompanied by transient elevation of intracellular EGFR and marked growth inhibition. IFN-α treated cancer cells were still sensitive to EGF proliferative stimulation. Conclusions: Our results indicate that cytostatic concentrations of IFN-α can enhance cell surface and intracellular EGFR expression in a proportion of human colon cancer cells. The antiproliferative action of IFN-α could not block the signal transduction of the EGF-EGFR pathway. This may have clinical implications for improving treatment based on targeting of EGFR.