Cancers

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Open AccessArticle

Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission

by Rada M. Grubovikj, Asif Alavi, Ahrin Koppel, Mary Territo and Gary J. Schiller

Cancers 2012, 4(2), 601-617; https://doi.org/10.3390/cancers4020601 - 20 Jun 2012

Cited by 11 | Viewed by 7479

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with [...] Read more.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45–7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0–14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS. Full article

(This article belongs to the Special Issue Leukemia)

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Open AccessArticle

Substantially Modified Ratios of Effector to Regulatory T Cells During Chemotherapy in Ovarian Cancer Patients Return to Pre-Treatment Levels at Completion: Implications for Immunotherapy

by Anthony Park, Chindu Govindaraj, Sue D. Xiang, Julene Halo, Michael Quinn, Karen Scalzo-Inguanti and Magdalena Plebanski

Cancers 2012, 4(2), 581-600; https://doi.org/10.3390/cancers4020581 - 18 Jun 2012

Cited by 11 | Viewed by 7239

Abstract

Ovarian cancer is the leading cause of death from gynaecological malignancy. Despite improved detection and treatment options, relapse rates remain high. Combining immunotherapy with the current standard treatments may provide an improved prognosis, however, little is known about how standard chemotherapy affects immune [...] Read more.

Ovarian cancer is the leading cause of death from gynaecological malignancy. Despite improved detection and treatment options, relapse rates remain high. Combining immunotherapy with the current standard treatments may provide an improved prognosis, however, little is known about how standard chemotherapy affects immune potential (particularly T cells) over time, and hence, when to optimally combine it with immunotherapy (e.g., vaccines). Herein, we assess the frequency and ratio of CD8+ central memory and effector T cells as well as CD4+ effector and regulatory T cells (Tregs) during the first 18 weeks of standard chemotherapy for ovarian cancer patients. In this pilot study, we observed increased levels of recently activated Tregs with tumor migrating ability (CD4+CD25^hiFoxp3+CD127−CCR4+CD38+ cells) in patients when compared to controls. Although frequency changes of Tregs as well as the ratio of effector T cells to Tregs were observed during treatment, the Tregs consistently returned to pre-chemotherapy levels at the end of treatment. These results indicate T cell subset distributions associated with recurrence may be largely resistant to being “re-set” to healthy control homeostatic levels following standard treatments. However, it may be possible to enhance T effector to Treg ratios transiently during chemotherapy. These results suggest personalized immune monitoring maybe beneficial when combining novel immuno-therapeutics with standard treatment for ovarian cancer patients. Full article

(This article belongs to the Special Issue Cancer Vaccines and Immunotherapy)

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Open AccessArticle

An Estimation of Radiobiological Parameters for Head-and-Neck Cancer Cells and the Clinical Implications

by X. Sharon Qi, Qiuhui Yang, Steve P. Lee, X. Allen Li and Dian Wang

Cancers 2012, 4(2), 566-580; https://doi.org/10.3390/cancers4020566 - 15 Jun 2012

Cited by 19 | Viewed by 6170

Abstract

In vitro survival measurements using two human head-and-neck cancer (HNC) cell lines were performed. The specially designed split-dose surviving fraction was obtained and fitted to the linear-quadratic formalism. The repair halftime (Tr), the potential doubling time (T_d), a/β and radiosensitivity a, [...] Read more.

In vitro survival measurements using two human head-and-neck cancer (HNC) cell lines were performed. The specially designed split-dose surviving fraction was obtained and fitted to the linear-quadratic formalism. The repair halftime (Tr), the potential doubling time (T_d), a/β and radiosensitivity a, were estimated. Other radiobiological models: EUD, BED, TCP, etc., were used to examine the potential treatment effectiveness of different IMRT techniques. Our data indicated the repair halftime of ~17 min based on two HNC cell lines. The combined a/β, a and T_d are a/β = 8.1 ± 4.1 Gy, a = 0.22 ± 0.08 Gy⁻¹, T_d = 4.0 ± 1.8 day, respectively. The prolonged IMRT dose delivery for entire HNC treatment course could possibly result in the loss of biological effectiveness, i.e., the target EUDs decreased by 11% with fraction dose delivery time varying from 5 to 30 min. We determined the sublethal damage repair halftime and other radiobiological parameters for HNC cells, and to evaluate treatment effectiveness of the prolonged dose delivery times associated with different IMRT techniques. The estimated repair halftime for HNC is relatively short and may be comparable to the step-and-shoot IMRT fraction dose delivery time. The effectiveness of IMRT treatment may be improved by reducing the fraction delivery time for HNC treatment. Full article

(This article belongs to the Special Issue Radiation and Cancers)

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Open AccessReview

Potentiality and Boundaries of Use of Sorafenib in Patients with Hepatocellular Carcinoma: Awaiting the Results of Ongoing Clinical Trials

by Massimo Di Maio, Gennaro Daniele, Maria Carmela Piccirillo, Pasqualina Giordano, Giuseppe Signoriello, Bruno Daniele and Francesco Perrone

Cancers 2012, 4(2), 549-565; https://doi.org/10.3390/cancers4020549 - 05 Jun 2012

Cited by 1 | Viewed by 6644

Abstract

No systemic therapy had been proven effective in patients with advanced hepatocellular carcinoma (HCC) until 2007, when a large randomized trial with sorafenib demonstrated a clinically relevant prolongation of survival. Currently, sorafenib represents standard treatment for patients with advanced HCC and well-preserved liver [...] Read more.

No systemic therapy had been proven effective in patients with advanced hepatocellular carcinoma (HCC) until 2007, when a large randomized trial with sorafenib demonstrated a clinically relevant prolongation of survival. Currently, sorafenib represents standard treatment for patients with advanced HCC and well-preserved liver function, whilst the evidence about its effectiveness in patients with more severe liver impairment is less robust. A randomized trial to demonstrate the efficacy of sorafenib in Child-Pugh B patients with advanced HCC is currently ongoing. In the meantime, several trials are testing the role of sorafenib in early HCC (as adjuvant treatment after potentially curative loco-regional therapies) and in intermediate stage (exploring different modalities of integration of sorafenib with trans-arterial chemo-embolization). The results of all these trials will better define the potentiality and the boundaries of use of sorafenib in HCC patients. Full article

(This article belongs to the Special Issue Advances and Research Progress in Hepatocellular Carcinoma)

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Open AccessReview

The Stroma—A Key Regulator in Prostate Function and Malignancy

by Christina Hägglöf and Anders Bergh

Cancers 2012, 4(2), 531-548; https://doi.org/10.3390/cancers4020531 - 29 May 2012

Cited by 51 | Viewed by 6912

Abstract

Prostate cancer is a very common and highly unpredictable form of cancer. Whereas many prostate cancers are slow growing and could be left without treatment, others are very aggressive. Additionally, today there is no curative treatment for prostate cancer patients with local or [...] Read more.

Prostate cancer is a very common and highly unpredictable form of cancer. Whereas many prostate cancers are slow growing and could be left without treatment, others are very aggressive. Additionally, today there is no curative treatment for prostate cancer patients with local or distant metastasis. Identification of new, improved prognostic and diagnostic biomarkers for prostate cancer and the finding of better treatment strategies for metastatic prostate cancer is therefore highly warranted. Interactions between epithelium and stroma are known to be important already during prostate development and this interplay is critical also in development, progression of primary tumors and growth of metastases. It is therefore reasonable to expect that future biomarkers and therapeutic targets can be identified in the prostate tumor and metastasis stroma and this possibility should be further explored. Full article

(This article belongs to the Special Issue Tumor Stroma)

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Open AccessReview

Epidermal to Mesenchymal Transition and Failure of EGFR-Targeted Therapy in Glioblastoma

by Andrej Pala, Georg Karpel-Massler, Richard Eric Kast, Christian Rainer Wirtz and Marc-Eric Halatsch

Cancers 2012, 4(2), 523-530; https://doi.org/10.3390/cancers4020523 - 08 May 2012

Cited by 25 | Viewed by 8427

Abstract

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor’s molecular biology and [...] Read more.

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor’s molecular biology and pathophysiology, which unfortunately has so far failed to translate into a meaningful clinical benefit. Dysregulation and a resulting prominent pathophysiological role of the epidermal growth factor receptor (EGFR) have been identified in several different malignant tumor entities, GBM among them. The EGFR is overexpressed in about 40% of GBM cases, and half of these coexpress a mutant, constitutively activated subtype, EGFRvIII. Unfortunately, recent trials studying with therapeutic approaches targeted against the EGFR and EGFRvIII have failed to meet expectations, with only a minority of patients responding despite evidence of good in vitro and rodent model activity. Having potentially high relevance within this context, epithelial to mesenchymal transition (EMT) is a phenomenon associated with early stages of carcinogenesis, cancer invasion and recurrence. During EMT, epithelial cells lose many of their epithelial characteristics, prominently E-cadherin expression, and acquire properties that are typical for mesenchymal cells such as the expression of vimentin. Epithelial to mesenchymal transition has been specifically demonstrated in GBM. In this review, we summarize the evidence that EMT may precipitate GBM resistance to EGFR-targeted therapy, and may thus be among the principal factors contributing to the clinical failure of targeted therapy against EGFR and EGFRvIII. Full article

(This article belongs to the Special Issue Cancer Diagnosis and Targeted Therapy)

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Open AccessReview

Gastroenteropancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1

by Francesco Tonelli, Francesco Giudici, Francesca Giusti and Maria Luisa Brandi

Cancers 2012, 4(2), 504-522; https://doi.org/10.3390/cancers4020504 - 07 May 2012

Cited by 13 | Viewed by 7234

Abstract

We reviewed the literature about entero-pancreatic neuroendocrine tumors in Multiple Endocrine Neoplasia type 1 syndrome (MEN1) to clarify their demographic features, localization imaging, practice, and appropriate therapeutical strategies, analyzing the current approach to entero-pancreatic neuroendocrine tumors in MEN1. Despite the fact that hyperparathyroidism [...] Read more.

We reviewed the literature about entero-pancreatic neuroendocrine tumors in Multiple Endocrine Neoplasia type 1 syndrome (MEN1) to clarify their demographic features, localization imaging, practice, and appropriate therapeutical strategies, analyzing the current approach to entero-pancreatic neuroendocrine tumors in MEN1. Despite the fact that hyperparathyroidism is usually the first manifestation of MEN1, the penetrance of these tumors is similar. They are characterized by multiplicity of lesions, variable expression of the tumors, and propensity for malignant degeneration. Both the histological type and the size of MEN1 neuroendocrine tumors correlate with malignancy. Monitoring of pancreatic peptides and use of imaging exams allow early diagnosis and prompt surgical treatment, resulting in prevention of metastatic disease and improvement of long-term survival. Surgery is often the treatment of choice for MEN1-neuroendocrine tumors. The rationale for surgical approach is to curtail malignant progression of the disease, and to cure the associated biochemical syndrome, should it be present. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors)

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Open AccessArticle

T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

by Oliver Abschuetz, Wolfram Osen, Kathrin Frank, Masashi Kato, Dirk Schadendorf and Viktor Umansky

Cancers 2012, 4(2), 490-503; https://doi.org/10.3390/cancers4020490 - 26 Apr 2012

Cited by 12 | Viewed by 8186

Abstract

Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse [...] Read more.

Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy. Full article

(This article belongs to the Special Issue Tumor Stroma)

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Open AccessArticle

P190B RhoGAP Regulates Chromosome Segregation in Cancer Cells

by Melissa Hwang, Sirisha Peddibhotla, Peter McHenry, Peggy Chang, Zachary Yochum, Ko Un Park, James Cooper Sears and Tracy Vargo-Gogola

Cancers 2012, 4(2), 475-489; https://doi.org/10.3390/cancers4020475 - 25 Apr 2012

Cited by 4 | Viewed by 7140

Abstract

Rho GTPases are overexpressed and hyperactivated in many cancers, including breast cancer. Rho proteins, as well as their regulators and effectors, have been implicated in mitosis, and their altered expression promotes mitotic defects and aneuploidy. Previously, we demonstrated that p190B Rho GTPase activating [...] Read more.

Rho GTPases are overexpressed and hyperactivated in many cancers, including breast cancer. Rho proteins, as well as their regulators and effectors, have been implicated in mitosis, and their altered expression promotes mitotic defects and aneuploidy. Previously, we demonstrated that p190B Rho GTPase activating protein (RhoGAP) deficiency inhibits ErbB2-induced mammary tumor formation in mice. Here we describe a novel role for p190B as a regulator of mitosis. We found that p190B localized to centrosomes during interphase and mitosis, and that it is differentially phosphorylated during mitosis. Knockdown of p190B expression in MCF-7 and Hela cells increased the incidence of aberrant microtubule-kinetochore attachments at metaphase, lagging chromosomes at anaphase, and micronucleation, all of which are indicative of aneuploidy. Cell cycle analysis of p190B deficient MCF-7 cells revealed a significant increase in apoptotic cells with a concomitant decrease in cells in G1 and S phase, suggesting that p190B deficient cells die at the G1 to S transition. Chemical inhibition of the Rac GTPase during mitosis reduced the incidence of lagging chromosomes in p190B knockdown cells to levels detected in control cells, suggesting that aberrant Rac activity in the absence of p190B promotes chromosome segregation defects. Taken together, these data suggest that p190B regulates chromosome segregation and apoptosis in cancer cells. We propose that disruption of mitosis may be one mechanism by which p190B deficiency inhibits tumorigenesis. Full article

(This article belongs to the Special Issue Tumor Stroma)

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Open AccessReview

Radical Decisions in Cancer: Redox Control of Cell Growth and Death

by Rosa M. Sainz, Felipe Lombo and Juan C. Mayo

Cancers 2012, 4(2), 442-474; https://doi.org/10.3390/cancers4020442 - 25 Apr 2012

Cited by 67 | Viewed by 9584

Abstract

Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed [...] Read more.

Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed that free radicals play a further complex role in cancer. Low levels of free radicals and steady state levels of antioxidant enzymes are responsible for the fine tuning of redox status inside cells. A change in redox state is a way to modify the physiological status of the cell, in fact, a more reduced status is found in resting cells while a more oxidative status is associated with proliferative cells. The mechanisms by which redox status can change the proliferative activity of cancer cells are related to transcriptional and posttranscriptional modifications of proteins that play a critical role in cell cycle control. Since cancer cells show higher levels of free radicals compared with their normal counterparts, it is believed that the anti-oxidative stress mechanism is also increased in cancer cells. In fact, the levels of some of the most important antioxidant enzymes are elevated in advanced status of some types of tumors. Anti-cancer treatment is compromised by survival mechanisms in cancer cells and collateral damage in normal non-pathological tissues. Though some resistance mechanisms have been described, they do not yet explain why treatment of cancer fails in several tumors. Given that some antitumoral treatments are based on the generation of free radicals, we will discuss in this review the possible role of antioxidant enzymes in the survival mechanism in cancer cells and then, its participation in the failure of cancer treatments. Full article

(This article belongs to the Special Issue Cell Death and Cancer)

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Open AccessReview

Immune Response to Sipuleucel-T in Prostate Cancer

by Eddie Thara, Tanya B. Dorff, Monica Averia-Suboc, Michael Luther, Mary E. Reed, Jacek K. Pinski and David I. Quinn

Cancers 2012, 4(2), 420-441; https://doi.org/10.3390/cancers4020420 - 18 Apr 2012

Cited by 10 | Viewed by 7189

Abstract

Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen [...] Read more.

Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients’ own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for immunotherapy, patient selection and best sequencing with other prostate cancer therapies remain to be determined. A better understanding of immune response may help address these issues. Full article

(This article belongs to the Special Issue Immune Responses to Human Prostate Cancer)

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Open AccessReview

The Dynamics of Developmental and Tumor Angiogenesis—A Comparison

by Yi Jin and Lars Jakobsson

Cancers 2012, 4(2), 400-419; https://doi.org/10.3390/cancers4020400 - 11 Apr 2012

Cited by 7 | Viewed by 6054

Abstract

The blood vasculature in cancers has been the subject of intense interest during the past four decades. Since the original ideas of targeting angiogenesis to treat cancer were proposed in the 1970s, it has become evident that more knowledge about the role of [...] Read more.

The blood vasculature in cancers has been the subject of intense interest during the past four decades. Since the original ideas of targeting angiogenesis to treat cancer were proposed in the 1970s, it has become evident that more knowledge about the role of vessels in tumor biology is needed to fully take advantage of such strategies. The vasculature serves the surrounding tissue in a multitude of ways that all must be taken into consideration in therapeutic manipulation. Aspects of delivery of conventional cytostatic drugs, induction of hypoxia affecting treatment by radiotherapy, changes in tumor cell metabolism, vascular leak and trafficking of leukocytes are affected by interventions on vascular function. Many tumors constitute a highly interchangeable milieu undergoing proliferation, apoptosis, and necrosis with abundance of growth factors, enzymes and metabolites. These aspects are reflected by the abnormal tortuous, leaky vascular bed with detached mural cells (pericytes). The vascular bed of tumors is known to be unstable and undergoing remodeling, but it is not until recently that this has been dynamically demonstrated at high resolution, facilitated by technical advances in intravital microscopy. In this review we discuss developmental genetic loss-of-function experiments in the light of tumor angiogenesis. We find this a valid comparison since many studies phenocopy the vasculature in development and tumors. Full article

(This article belongs to the Special Issue Tumor Stroma)

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Open AccessReview

External Beam Radiotherapy of Recurrent Glioma: Radiation Tolerance of the Human Brain

by Peter Sminia and Ramona Mayer

Cancers 2012, 4(2), 379-399; https://doi.org/10.3390/cancers4020379 - 05 Apr 2012

Cited by 51 | Viewed by 8345

Abstract

Malignant gliomas relapse in close proximity to the resection site, which is the postoperatively irradiated volume. Studies on re-irradiation of glioma were examined regarding radiation-induced late adverse effects (i.e., brain tissue necrosis), to obtain information on the tolerance dose and treatment [...] Read more.

Malignant gliomas relapse in close proximity to the resection site, which is the postoperatively irradiated volume. Studies on re-irradiation of glioma were examined regarding radiation-induced late adverse effects (i.e., brain tissue necrosis), to obtain information on the tolerance dose and treatment volume of normal human brain tissue. The studies were analyzed using the linear-quadratic model to express the re-irradiation tolerance in cumulative equivalent total doses when applied in 2 Gy fractions (EQD2_cumulative). Analysis shows that the EQD2_cumulative increases from conventional re-irradiation series to fractionated stereotactic radiotherapy (FSRT) to LINAC-based stereotactic radiosurgery (SRS). The mean time interval between primary radiotherapy and the re-irradiation course was shortened from 30 months for conventional re-irradiation to 17 and 10 months for FSRT and SRS, respectively. Following conventional re-irradiation, radiation-induced normal brain tissue necrosis occurred beyond an EQD2_cumulative around 100 Gy. With increasing conformality of therapy, the smaller the treatment volume is, the higher the radiation dose that can be tolerated. Despite the dose escalation, no increase in late normal tissue toxicity was reported. On basis of our analysis, the use of particle therapy in the treatment of recurrent gliomas, because of the optimized physical dose distribution in the tumour and surrounding healthy brain tissue, should be considered for future clinical trials. Full article

(This article belongs to the Special Issue Re-Irradiation, Chemotherapy, New Drugs for the (Re)-Treatment of Recurrent Gliomas)

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Open AccessReview

A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase

by Venturina Stagni, Simonetta Santini and Daniela Barilà

Cancers 2012, 4(2), 354-378; https://doi.org/10.3390/cancers4020354 - 05 Apr 2012

Cited by 5 | Viewed by 6667

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCCs are genetically and phenotypically heterogeneous tumors characterized by very poor prognosis, mainly due to the lack, at present, of effective therapeutic options, as these tumors are rarely suitable for radiotherapy and [...] Read more.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCCs are genetically and phenotypically heterogeneous tumors characterized by very poor prognosis, mainly due to the lack, at present, of effective therapeutic options, as these tumors are rarely suitable for radiotherapy and often resistant to chemotherapy protocols. In the last years, agonists targeting the Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) death receptor, has been investigated as a valuable promise for cancer therapy, based on their selectivity for malignant cells and low toxicity for healthy cells. However, many cancer models display resistance to death receptor induced apoptosis, pointing to the requirement for the development of combined therapeutic approaches aimed to selectively sensitize cancer cells to TRAIL. Recently, we identified ATM kinase as a novel modulator of the ability of chemotherapeutic agents to enhance TRAIL sensitivity. Here, we review the biological determinants of HCC responsiveness to TRAIL and provide an exhaustive and updated analysis of the molecular mechanisms exploited for combined therapy in this context. The role of ATM kinase as potential novel predictive biomarker for combined therapeutic approaches based on TRAIL and chemotherapeutic drugs will be closely discussed. Full article

(This article belongs to the Special Issue Advances and Research Progress in Hepatocellular Carcinoma)

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Open AccessReview

Remodeling of Tumor Stroma and Response to Therapy

by Anna Johansson and Ruth Ganss

Cancers 2012, 4(2), 340-353; https://doi.org/10.3390/cancers4020340 - 27 Mar 2012

Cited by 12 | Viewed by 7888

Abstract

Solid tumors are intrinsically resistant to therapy. Cancer progression occurs when tumor cells orchestrate responses from diverse stromal cell types such as blood vessels and their support cells, inflammatory cells, and fibroblasts; these cells collectively form the tumor microenvironment and provide direct support [...] Read more.

Solid tumors are intrinsically resistant to therapy. Cancer progression occurs when tumor cells orchestrate responses from diverse stromal cell types such as blood vessels and their support cells, inflammatory cells, and fibroblasts; these cells collectively form the tumor microenvironment and provide direct support for tumor growth, but also evasion from cytotoxic, immune and radiation therapies. An indirect result of abnormal and leaky blood vessels in solid tumors is high interstitial fluid pressure, which reduces drug penetration, but also creates a hypoxic environment that further augments tumor cell growth and metastatic spread. Importantly however, studies during the last decade have shown that the tumor stroma, including the vasculature, can be modulated, or re-educated, to allow better delivery of chemotherapeutic drugs or enhance the efficiency of active immune therapy. Such remodeling of the tumor stroma using genetic, pharmacological and other therapeutic approaches not only enhances selective access into tumors but also reduces toxic side effects. This review focuses on recent novel concepts to modulate tumor stroma and thus locally increase therapeutic efficacy. Full article

(This article belongs to the Special Issue Tumor Stroma)

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Open AccessArticle

Micronutrient Synergy in the Fight against Hepatocellular Carcinoma

by M. Waheed Roomi, Nusrath W. Roomi, Tatiana Kalinovsky, Aleksandra Niedzwiecki and Matthias Rath

Cancers 2012, 4(2), 323-339; https://doi.org/10.3390/cancers4020323 - 23 Mar 2012

Cited by 7 | Viewed by 6594

Abstract

The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment [...] Read more.

The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM) synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay), MMPs secretion (by gelatinase zymography), cell invasion (through Matrigel) and induction of apoptosis (by live green caspase). In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography) and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography) in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA) induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and progression, such as proliferation, invasion and metastasis, and by inducing apoptosis. Full article

(This article belongs to the Special Issue Advances and Research Progress in Hepatocellular Carcinoma)

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Cancers, Volume 4, Issue 2 (June 2012) – 16 articles , Pages 323-617

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