Stanley S. Stylli

Invadopodia: At the cutting edge of tumour invasion

Invasion of tissues by malignant tumours is facilitated by tumour cell migration and degradation of extracellular matrix (ECM) barriers. Several invasive neoplasms, including head and neck squamous cell carcinoma, breast carcinoma, melanoma and glioma, contain tumour cells that can form actin-rich protrusions with ECM proteolytic activity called invadopodia. These dynamic organelle-like structures adhere to, and digest, collagens, laminins and fibronectin. Invadopodia are dependent on multiple transmembrane, cytoplasmic and secreted proteins engaged in cell adhesion, signal transduction, actin assembly, membrane regulation and ECM proteolysis. Strategies aimed at disrupting invadopodia could form the basis of novel anti-invasive therapies for treating patients. Here we review the molecular basis of invadopodia formation with particular emphasis on the intracellular signaling networks that are essential for invadopodia activity and examine the potential role of these structures in glioma invasion.

Photodynamic therapy of high grade glioma - long term survival

Haemetaporphyrin derivative (HpD) mediated photodynamic therapy (PDT) has been investigated as an adjuvant treatment for cerebral glioma. This study records the survival of patients at the Royal Melbourne Hospital with residences in the State of Victoria, utilizing the Victorian Cancer Registry database for patients treated with adjuvant PDT following surgical resection of the tumour. For primary (newly diagnosed) tumours, median survival from initial diagnosis was 76.5 months for anaplastic astrocytoma (AA) and 14.3 months for glioblastoma multiforme (GBM). Seventy-three percent of patients with AA and 25% with GBM survived longer than 36 months. For recurrent tumour, median survival from the time of surgery was 66.6 months for AA and 13.5 months for GBM. Fifty-seven percent of patients with recurrent AA and 41% of patients with recurrent GBM survived longer than 36 months. Older age at the time of diagnosis was associated with poorer prognosis. Laser light doses above the sample median of 230 J/cm2 were associated with better prognosis in the 136 patients studied (primary tumour patients - (HR=0.50[0.27,0.95],p=0.033); recurrent tumour patients (HR=0.75[0.42,1.31],p=0.312). There was no mortality directly associated with the therapy, three patients had increased cerebral oedema thought to be related to photodynamic therapy that was controlled with conventional therapies.

Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation

Invadopodia are actin-based projections enriched with proteases, which invasive cancer cells use to degrade the extracellular matrix (ECM). The Phox homology (PX)-Src homology (SH)3 domain adaptor protein Tks5 (also known as SH3PXD2A) cooperates with Src tyrosine kinase to promote invadopodia formation but the underlying pathway is not clear. Here we show that Src phosphorylates Tks5 at Y557, inducing it to associate directly with the SH3-SH2 domain adaptor proteins Nck1 and Nck2 in invadopodia. Tks5 mutants unable to bind Nck show reduced matrix degradation-promoting activity and recruit actin to invadopodia inefficiently. Conversely, Src- and Tks5-driven matrix proteolysis and actin assembly in invadopodia are enhanced by Nck1 or Nck2 overexpression and inhibited by Nck1 depletion. We show that clustering at the plasma membrane of the Tks5 inter-SH3 region containing Y557 triggers phosphorylation at this site, facilitating Nck recruitment and F-actin assembly. These results identify a Src-Tks5-Nck pathway in ECM-degrading invadopodia that shows parallels with pathways linking several mammalian and pathogen-derived proteins to local actin regulation.

Photodynamic therapy of cerebral glioma – A review Part II – Clinical studies

Photodynamic therapy (PDT) is a binary treatment modality that has been used to treat malignant brain tumours for 25 years. The treatment involves the selective uptake of a photosensitizer (PS) by the tumour cells followed by irradiation of the tumour with light of the appropriate wavelength to excite and activate the PS resulting in selective tumour destruction and is a potentially valuable adjunct to surgical excision and other conventional therapies. PDT has undergone extensive laboratory studies and clinical trials with a variety of PS and tumour models. These are discussed with reference mainly to clinical studies involving the PDT of brain tumours.

Phase I and Pharmacokinetic Study of Photodynamic Therapy for High-Grade Gliomas Using a Novel Boronated Porphyrin

PURPOSE To determine the recommended dose, toxicity profile, and pharmacokinetics of a novel boronated porphyrin (BOPP) for photodynamic therapy (PDT) of intracranial tumors. PATIENTS AND METHODS BOPP was administered alone in increasing doses (0.25, 0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg) preoperatively in patients with intracranial tumors undergoing postresection PDT until dose-limiting toxicity (DLT) was observed. RESULTS Twenty-nine assessable patients with intracranial tumors received BOPP intravenously 24 hours before surgery. The recommended dose was 4 mg/kg. Dose escalation was limited by thrombocytopenia. The most common nonhematologic toxicity was skin photosensitivity. Pharmacokinetic parameters showed increased area under the plasma concentration-time curve and maximum concentration with increased dose. Tumor BOPP concentrations also increased with increased dose. CONCLUSION BOPP at a dose of 4 mg/kg was well tolerated. DLT was thrombocytopenia, and photosensitivity was the only other toxicity of note. The efficacy of PDT using BOPP requires further exploration.

Photodynamic therapy of brain tumours: evaluation of porphyrin uptake versus clinical outcome.

The objective of this study was to investigate whether the level of the photosensitizer haematoporphyrin derivative (HpD) uptake measured in tissue samples taken from brain tumour patients was associated with survival post-treatment with photodynamic therapy (PDT). The mean HpD uptake in tumour tissue was significantly higher in glioblastoma multiforme than anaplastic astrocytoma. Recurrent tumours had a higher mean uptake compared to primary tumours, which was evident in all grades of tumour. Among patients with GBM, there was a significant association between greater HpD uptake and survival (HR = 0.26 [0.12, 0.59], p = 0.001). There was also some evidence of a weak association between greater HpD uptake and survival among patients with AA, although the result was inconclusive (HR = 0.73 [0.32, 1.71], p = 0.472).

The role of Stat3 in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common brain tumor and has the worst prognosis. Several signaling molecules have been clearly implicated in the development, progression, and aggressiveness of GBM. Here we review the role of signal transducer and activator of transcription-3 (Stat3) in GBM. We particularly focus on its expression in clinical GBM samples, its role in brain tumorigenicity in cell lines and animal models, and discuss possible therapeutic strategies targeting Stat3. This review also summarizes the current knowledge regarding the role of Stat3 regulation by upstream activators and repressors in promoting GBM progression in both translational and clinical studies.

Photodynamic therapy of cerebral glioma – A review Part I – A biological basis

Photodynamic therapy (PDT) has been investigated extensively in the laboratory for decades, and for over 25 years in the clinical environment, establishing it as a useful adjuvant to standard treatments for many cancers. A combination of both photochemical and photobiological processes occur that lead to the eventual selective destruction of the tumour cells. It is a potentially valuable adjuvant therapy that can be used in conjunction with other conventional therapies for the treatment of cerebral glioma. PDT has undergone extensive laboratory studies and clinical trials with a variety of photosensitizers (PS) and tumour models of cerebral glioma. Many environmental and genetically based factors influence the outcome of the PDT response. The biological basis of PDT is discussed with reference to laboratory and preclinical studies.

The Role of STAT3 Signaling in Mediating Tumor Resistance to Cancer Therapy

Signal transducer and activator of transcription 3 (STAT3) is activated in many cancer types and can regulate pathways involving tumorigenesis, cell proliferation, cell survival and angiogenesis. Upstream cytokine signaling through multiple trans-membrane receptors can enhance the activation of STAT3 and promote tumor progression. Importantly, STAT3 activation can also be induced via the Janus-activated kinase 1/2 (JAK1/2) and Src family kinases. Target-specific drug therapies have been developed to inhibit many of the upstream receptor and non-receptor activators of STAT3 and are now approved for clinical use. Recently, resistance to standard-of-care therapies has been linked to constitutive or unabated STAT3 activation, suggesting that combination therapy with STAT3 inhibitors may be of clinical benefit. Furthermore, STAT3 activity has also been shown to regulate self-renewal of cancer stem cells that are often refractory to chemotherapy treatment. This review will focus on STAT3 mediated resistance to cancer therapy and discuss strategies to overcome this resistance.

Prognostic significance of Tks5 expression in gliomas

A pathological hallmark of gliomas is their extensive invasion into the brain parenchyma regardless of tumour grade. Clinically this is a major factor in tumour recurrence as surgery and adjuvant therapies are unable to eradicate all the infiltrating malignant cells. Tyrosine kinase substrate with five SH3 domains (Tks5, also known as SH3PXD2A) and cortactin are required for the formation of invadopodia, actin-based protrusions of tumour cells with associated proteolytic activity implicated in tumour invasion. We investigated the prognostic significance of Tks5 and cortactin expression in 57 patients with various grades of glioma. Expression of Tks5 or cortactin occurred in all grades of tumours and expression of Tks5, but not cortactin, was associated with significantly reduced patient survival among glioma patients. This association was clearest in patients with low-grade astrocytomas and oligoastrocytomas. These results suggest a prognostic relevance for the Tks5 invadopodial protein in glial-derived brain tumours.