http://kitto.cm.utexas.edu/courses/ch395g/fall2009/MOL190/LoPiccolo.pdf

Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations

Phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway play an important role in multiple cellular functions such as cell metabolism, proliferation, cell-cycle progression, and survival. PI3K is activated by growth factors and angiogenesis inducers such as vascular endothelial growth factor (VEGF) and angiopoietins. The amplification and mutations of PI3K and the loss of the tumor suppressor PTEN are common in various kinds of human solid tumors. The genetic alterations of upstream and downstream of PI3K signaling molecules such as receptor tyrosine kinases and AKT, respectively, are also frequently altered in human cancer. PI3K signaling regulates tumor growth and angiogenesis by activating AKT and other targets, and by inducing HIF-1 and VEGF expression. Angiogenesis is required for tumor growth and metastasis. In this review, we highlight the recent studies on the roles and mechanisms of PI3K and PTEN in regulating tumorigenesis and angiogenesis, and the roles of the downstream targets of PI3K for transmitting the signals. We also discuss the crosstalk of these signaling molecules and cellular events during tumor growth, metastasis, and tumor angiogenesis. Finally, we summarize the potential applications of PI3K, AKT, and mTOR inhibitors and their outcome in clinical trials for cancer treatment.

PI3K/PTEN signaling in angiogenesis and tumorigenesis

Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises.

Background: Preoperative systemic chemotherapy is increasingly used in patients who undergo hepatic resection for colorectal liver metastases (CLM). Although chemotherapy-related hepatic injury has been reported, the incidence and the effect of such injury on patient outcome remain ill defined. Methods: A systematic review of relevant studies published before May 2006 was performed. Studies that reported on liver injury associated with preoperative chemotherapy for CLM were identified and data on chemotherapy-specific liver injury and patient outcome following hepatic resection were synthesized and tabulated. Results: Hepatic steatosis, a mild manifestation of non-alcoholic fatty liver disease (NAFLD), may occur after treatment with 5-fluorouracil and is associated with increased postoperative morbidity. Nonalcoholic steatohepatitis, a serious complication of NAFLD that includes inflammation and hepatocyte damage, can occur after treatment with irinotecan, especially in obese patients. Irinotecan-associated steatohepatitis can affect hepatic reserve and increase morbidity and mortality after hepatectomy. Hepatic sinusoidal obstruction syndrome can occur in patients treated with oxaliplatin, but does not appear to be associated with an increased risk of perioperative death. Conclusion: Preoperative chemotherapy for CLM induces regimen-specific hepatic changes that can affect patient outcome. Both response rate and toxicity should be considered when selecting preoperative chemotherapy in patients with CLM.

https://bjssjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/bjs.5719

Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases

Directed migration or chemotaxis of arterial smooth muscle cells (SMC) contributes to intimal SMC accumulation, a key event in the development of atherosclerotic lesions and in restenosis after angioplasty. The present study compares and contrasts insulin-like growth factor I (IGF-I) and platelet-derived growth factor (PDGF-BB) as chemoattractants and mitogens for human arterial SMC. Compared with PDGF-BB, IGF-I is a weaker SMC mitogen. Thus, PDGF-BB, but not IGF-I, evokes a strong and rapid activation of mitogen-activated protein (MAP) kinase kinase and MAP kinase. However, IGF-I is a potent stimulator of directed migration of human arterial SMC, as measured in a Boyden chamber assay. The half-maximal concentration for migration is similar to the Kd for IGF-I receptor interaction. An IGF-I receptor-blocking antibody blocks the effects of IGF-I, IGF-II, and insulin, indicating that the effects are indeed mediated through the IGF-I receptor. The maximal effect of IGF-I on directed migration ranges between 50% and 100% of the effect of PDGF-BB, the strongest known chemoattractant for SMC. The ability of IGF-I and PDGF-BB to induce chemotaxis coincides with their ability to stimulate phosphatidylinositol turnover, diacylglycerol formation, and intracellular Ca2+ flux and suggests that these signaling pathways, but not activation of the MAP kinase cascade, are required for chemotaxis of human arterial SMC.

/pdf/insulin-like-growth-factor-i-and-platelet-derived-growth-5fzcwtb85u.pdf

Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation.

Objective This retrospective, nonrandomized review evaluates 125 patients with esophageal carcinoma (adenocarcinoma and squamous cell) who underwent either surgery only or preoperative chemotherapy and/or radiation therapy followed by surgery. Major end points were survival and postchemoradiation downstaging. Methods Forty-four patients underwent radiation therapy of 4500 cGy over 5 weeks. Fluorouracil and cisplatin were administered on the first and fifth week of radiotherapy. Ninety-eight patients underwent potentially curative resections-transhiatal esophagectomy (70), Lewis esophagogastrectomy (25), and left esophagogastrectomy (3). All patients with preoperative adjuvant therapy underwent endoscopy and biopsy before surgery. Results There were no differences in overall mortality (5%) or surgical complications in either group. Fourteen of 44 patients (32%) downstaged to complete pathologic response, with 5-year survival of 57%. Fifteen of 44 patients (34%) downstaged to microscopic residual tumor, with 1- and 3-year survival of 77% and 31%, respectively. Twenty-eight of 29 patients in the two downstaged groups were lymph node negative. Overall, 5-year survival in the adjuvant therapy plus surgery group versus surgery only was 36% and 11% (p = 0.04). Five-year survival in lymph node-negative adjuvant therapy and surgery patients was 49% (p = 0.005). Positive nodes in the surgery only group was 48% versus 23% in the adjuvant therapy and surgery group (p = 0.02). Conclusion Although retrospective and nonrandomized, these results suggest that preoperative chemoradiation results in significant clinical and pathologic downstaging, increases survival, and may sterilize local and regional lymph nodes, accounting for both downstaging and survival statistics.

Downstaging of esophageal cancer after preoperative radiation and chemotherapy.

The migration of retinal pigment epithelial (RPE) cells from their normal anatomic position to a new position in the vitreous cavity is a critical feature of proliferative vitreous retinopathy. To determine if insulin-like growth factor I (IGF I), which is present in the vitreous fluid of diabetics, stimulates RPE cells, we examined the effects of IGF I on the proliferation, chemotaxis, and release of plasminoqen activator by these cells.At the concentrations of IGF I tested, significant proliferation of RPE cells is seen. Significant chemotaxis of the RPE cells also is seen at all the concentrations of IGF I tested. The mean number of migrating cells per high-powered field in control studies was 43 ± 13 (x ± SEM), and for IGF I at 2.5 ng and 50 ng/ml the mean numbers of migrating cells were 96 ± 17 and 483 ± 62, respectively (P <0.001 for each comparison). The IGF I response was noted to be dose-dependent. The chemotactic response noted at 50 ng/ml of IGF I was greater than the positive chemotactic contr...

Insulin-like growth factor I stimulates proliferation, migration, and plasminogen activator release by human retinal pigment epithelial cells.

Background:Perifosine, a heterocyclic alkylphosphocholine signal transduction inhibitor, has activity against multiple cell types in vitro. This is a phase II study to determine activity and toxicity of perifosine in pancreatic adenocarcinoma.Patients and Methods:Previously untreated patients with l

A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma.

Small cell tumors are a heterogeneous group of neoplasms with similar morphologic features. They include lymphomas, carcinomas with variable degrees of neuroendocrine differentiation, rhabdomyosarcomas, and neuroblastomas. The authors describe a rare case of primitive neuroectodermal tumor (PNET) located in the kidney that was thoroughly studied with modern diagnostic techniques, including expression of protein P 30/32 MIC2 with the antibody 013 with subsequent demonstration of a genetic translocation consistent with t(11;22). The literature on small cell tumors of the kidney, with special emphasis on PNET, is reviewed.

Primary primitive neuroectodermal tumor of the kidney. Case report and review of the literature.

Epithelioid hemangioendothelioma is a rare vascular tumor with unpredictable behavior. It often presents as liver or lung nodules and is refractory to conventional chemotherapy. Surgical resection and/or liver transplantation have been the mainstay of therapy, but the results are mixed and unsatisfactory. Although the etiology of this malignancy is unknown, an increased incidence in women has been noted, and an association with exposure to vinyl chloride is emerging as a possible risk factor. This review proposes polyurethane/silicone breast implants as a potential cause of the condition and highlights the dramatic response to interferon (IFN)-alpha in a woman, so exposed, with widespread disease in the liver and lungs. The implications for other women who have had this type of implant could be significant, and the early use of IFN-alpha may be optimal.

Robert D. Marsh

Papers

Downstaging of esophageal cancer after preoperative radiation and chemotherapy.

Insulin-like growth factor I stimulates proliferation, migration, and plasminogen activator release by human retinal pigment epithelial cells.

A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma.

Primary primitive neuroectodermal tumor of the kidney. Case report and review of the literature.

Breast implants as a possible etiology of epithelioid hemangioendothelioma and successful therapy with interferon-alpha2.