Therapy For Gastrointestinal Cancers Research Articles

Particle Radiation Therapy for Gastrointestinal Cancers.

Particle irradiation of cancerous disease has gained great traction in recent years. The ability for particle therapy centers to deliver radiation with a highly conformal dose distribution while maintaining minimal exit or excess dose delivered to normal tissue, coupled with various biological advantages particularly found with heavy-ion beams, enables treatment of diseases inapproachable with conventional radiotherapy. Here, we present a review of the current status of particle therapy with regard to cancers of the gastrointestinal tract, including esophagus, liver, pancreas, and recurrent rectal cancer.

Local therapy for gastrointestinal cancer

Local therapy for gastrointestinal cancer

Chemoprevention of Low-Molecular-Weight Citrus Pectin (LCP) in Gastrointestinal Cancer Cells

Background & Aims: Low-molecular-weight citrus pectin (LCP) is a complex polysaccharide that displays abundant galactosyl (i.e., sugar carbohydrate) residues. In this study, we evaluated the anti-tumor properties of LCP that lead to Bcl-xL -mediated dampening of apoptosis in gastrointestinal cancer cells.Methods: We used AGS gastric cancer and SW-480 colorectal cancer cells to elucidate the effects of LCP on cell viability, cell cycle and apoptosis in cultured cells and tumor xenografts.Results: Significantly decreased cell viabilities were observed in LCP treated AGS and SW-480 cells (P<0.05). Cell cycle-related protein expression, such as Cyclin B1, was also decreased in LCP treated groups as compared to the untreated group. The AGS or SW-480 cell-line tumor xenografts were significantly smaller in the LCP treated group as compared the untreated group (P<0.05). LCP treatment decreased Galectin-3 (GAL-3) expression levels, which is an important gene in cancer metastasis that results in reversion of the epithelial-mesenchymal transition (EMT), and increased suppression of Bcl-xL and Survivin to promote apoptosis. Moreover, results demonstrated synergistic tumor suppressor activity of LCP and 5-FU against gastrointestinal cancer cells both in vivo and in vitro.Conclusions: LCP effectively inhibits the growth and metastasis of gastrointestinal cancer cells, and does so in part by down-regulating Bcl-xL and Cyclin B to promote apoptosis, and suppress EMT. Thus, LCP alone or in combination with other treatments has a high potential as a novel therapeutic strategy to improve the clinical therapy of gastrointestinal cancer.

Nausea and vomiting induced by gastrointestinal radiation therapy: current status and future directions.

Radiation therapy-induced nausea and vomiting (RINV) are common and troublesome symptoms among patients receiving radiation therapy for gastrointestinal cancers. Their impact on function, quality of life and, ultimately, cancer control warrant a review of their incidence, underlying mechanisms, treatments and research themes. Research in RINV is underrepresented relative to that in chemotherapy-induced nausea and vomiting. The incidence of RINV among patients receiving modern day radiation therapy is questioned and supportive care practice patterns vary among radiation oncologists. Antiemetic guideline recommendations for prophylactic and rescue therapy are based solely on the anatomic region being irradiated and not other patient-related, radiation therapy-related, or organ-specific dosimetric factors that likely modulate the risk of RINV. Dosimetric predictors are likely the most attainable biomarker moving forward, but only early steps have been taken. The small bowel and stomach will be the best first candidates for study among patients with gastrointestinal cancers. Studies of the mechanisms underlying RINV are conspicuously lacking. A new generation of observational studies and therapeutic clinical trials is needed, and more attention must be given to the relative impact of nausea and vomiting on the function and quality of life among specific homogeneous patient populations. Optimal supportive care strategies for RINV following radiation therapy for gastrointestinal cancers are lacking, and will not be known until future research answers the many open questions regarding the mechanisms underlying RINV, the true incidence and impact of these symptoms among patients and the best way to predict and mitigate them.

Honokiol confers immunogenicity by dictating calreticulin exposure, activating ER stress and inhibiting epithelial-to-mesenchymal transition

Peritoneal dissemination is a major clinical obstacle in gastrointestinal cancer therapy, and it accounts for the majority of cancer-related mortality. Calreticulin (CRT) is over-expressed in gastric tumors and has been linked to poor prognosis. In this study, immunohistochemistry studies revealed that the up-regulation of CRT was associated with lymph node and distant metastasis in patients with gastric cancer specimens. CRT was significantly down-regulated in highly metastatic gastric cancer cell lines and metastatic animal by Honokiol-treated. Small RNA interference blocking CRT by siRNA-CRT was translocated to the cells in the early immunogenic response to Honokiol. Honokiol activated endoplasmic reticulum (ER) stress and down-regulated peroxisome proliferator-activated receptor-γ (PPARγ) activity resulting in PPARγ and CRT degradation through calpain-II activity, which could be reversed by siRNA-calpain-II. The Calpain-II/PPARγ/CRT axis and interaction evoked by Honokiol could be blocked by gene silencing or pharmacological agents. Both transforming growth factor (TGF)-β1 and N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) induced cell migration, invasion and reciprocal down-regulation of epithelial marker E-cadherin, which could be abrogated by siRNA-CRT. Moreover, Honokiol significantly suppressed MNNG-induced gastrointestinal tumor growth and over-expression of CRT in mice. Knockdown CRT in gastric cancer cells was found to effectively reduce growth ability and metastasis in vivo. The present study provides insight into the specific biological behavior of CRT in epithelial-to-mesenchymal transition (EMT) and metastasis. Taken together, our results suggest that the therapeutic inhibition of CRT by Honokiol suppresses both gastric tumor growth and peritoneal dissemination by dictating early translocation of CRT in immunogenic cell death, activating ER stress, and blocking EMT.

高齢者に対する消化器領域の光線力学療法

高齢者に対する消化器領域の光線力学療法

Trends in clinical use of targeted therapy for gastrointestinal cancers

Targeted drugs therapies that block the molecular pathways involved in the development and progression of gastro-intestinal (GI) cancers have recently gained considerable attention. In addition to agents targeting vascular endothelial growth factor (VEGF), epidermal growth factor receptor, the multi-kinase inhibitor, and regorafenib have also become available for the treatment of metastatic colorectal cancer patients. Currently, trastuzumab, an antibody targeting human epidermal growth factor receptor-2 (HER-2), in combination with cytotoxic drugs is considered as the standard treatment for patients with HER-2 positive gastric cancer (GC). The efficacy of ramucirumab, a human monoclonal antibody that inhibits VEGF from binding to its receptor in GC, has also been recently demonstrated. At present, a great number of novel targeted drugs are in pre-clinical or clinical studies. In this review, we summarize trends in the use of molecularly targeted drugs that have proven to be effective for treating GI cancers, with a focus on emerging strategies for personalized treatment.

Long non-coding RNA LSINCT5 predicts negative prognosis and exhibits oncogenic activity in gastric cancer.

Long non-coding RNAs (lncRNAs) are recently discovered RNA transcripts that are aberrantly expressed in many tumor types. Numerous studies have suggested that lncRNAs can be utilized for cancer diagnosis and prognosis. LSINCT5 (long stress-induced non-coding transcript 5) is dramatically upregulated in breast and ovarian cancer and affects cellular proliferation. However, the expression pattern of LSINCT5 in gastrointestinal cancer and the association between aberrant expression of LSINCT5 in gastrointestinal cancer and malignancy, metastasis, or prognosis remain unknown. LSINCT5 expression was detected in gastrointestinal cancer and paired adjacent normal tissue samples or cell lines using reverse transcription quantitative PCR (RT-qPCR). We also investigated the potential relationship between tumor LSINCT5 levels and clinicopathological features of gastrointestinal cancer. Finally, we assessed whether LSINCT5 influences in vitro cell proliferation. The expression of LSINCT5 is significantly upregulated in gastrointestinal cancer tissues and cell lines relative to their normal counterparts. In addition, increased LSINCT5 expression was correlated with a larger tumor size, deeper tumor depth, and advanced clinical stage. Kaplan-Meier analysis indicated that gastric cancer (GC) and colorectal cancer (CRC) patients with higher LSINCT5 expression levels have worse disease-free survival (DFS) and disease-specific survival (DSS) rates. Moreover, multivariate analysis revealed that increased expression of LSINCT5 is an independent predictor of DFS and DSS rates in GC patients. The ectopic expression of LSINCT5 in gastrointestinal cancer cell lines resulted in an increase in cellular proliferation; conversely, knock down of LSINCT5 significantly inhibited proliferation. These results suggest that LSINCT5 may represent a novel prognostic indicator and a target for gene therapy in gastrointestinal cancer.

Targeting platelet-derived growth factor (PDGF) signaling in gastrointestinal cancers: preclinical and clinical considerations.

The prognosis of advanced gastrointestinal malignancies has been generally dreadful prompting robust search for better, more personalized, and more tailored treatments. In recent years, important signaling pathways leading to tumor progression and metastasis have been discovered with the subsequent development of targeted therapies to target these pathways. These include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), mammalian target of rapamycin (mTOR), and mesenchymal epithelial transition (MET). In this review, we will revise the different biological and clinical aspects related to the use of PDGF pathway-targeted therapies in gastrointestinal cancers with particular focus on the future prospective in that regard.

Combined-modality therapy in gastrointestinal cancers

Charles Richard Thomas Jr speaks to Theo Bond, Assistant Commissioning Editor: Charles Richard Thomas Jr is Professor and chair of the Department of Radiation Medicine and Professor of Hematology/Oncology in the Department of Medicine at the Oregon Health and Science University (OHSU) in Portland (OR, USA). He is also an active member of the OHSU Knight Cancer Institute (OR, USA). Thomas has received triple-board certification in Radiation Oncology (American Board of Radiology), Medical Oncology and Internal Medicine (American Board of Internal Medicine). He is a member of the NCI Rectal Anal Cancer Task Force. He also has an interest in cancer disparities and was one of the editors for the special edition on cancer disparities published in the Journal of Clinical Oncology in 2006. He is also active in protocol development either as chair or co-chair within the US co-operative group mechanism, with a focus on novel therapeutic and translational clinical research on gastrointestinal and thoracic malignancies that have tested incorporation of novel antiproliferative systemic agents with radiotherapy. Currently, Thomas has served as the chair of the Radiation Oncology Committee of the American College of Surgeons Oncology Group (ACOSOG). He has served as editor-in-chief of Radiation Medicine Rounds (Demos Medical Publishing), as well as on the Editorial Boards of a number of peer-reviewed journals. Thomas has served as an oral and written examiner for the gastrointestinal section of The American Board of Radiology Certification Examination, as well as on multiple committees within the American Society of Clinical Oncology (ASCO), American Association for Cancer Research (AACR), Radiological Society of North America (RSNA), American College of Radiology (ACR) and the American Society of Radiation Oncology (ASTRO). He is the author or co-author of over 145 journal articles and is a co-editor of multiple textbooks, including Mediastinal Tumors (1995), Biliary Tract &amp; Gallbladder Cancers: Diagnosis and Therapy (2008) and Esophagus Cancers: Practice and Principles (2009). His passion resides with mentoring the best and brightest talent, especially individuals from historically under-represented populations, in order to further develop the pipeline of highly skilled oncologists.

Proton therapy for gastrointestinal cancers

Proton beam therapy provides an opportunity to deliver ionizing radiation with improved dose conformity. It has gained popularity as a means of more localized radiation delivery. However, proton therapy data are still lacking, as there are still relatively few proton treatment centers worldwide. This paucity of data is particularly evident in gastrointestinal (GI) cancers. Most GI cancers are located in close proximity to or abut critical organs. The ability to deliver an appropriate dose to a target in this area is challenging; normal organ toxicities often limit the amount of radiation that can be delivered to achieve a therapeutic dose. The modern trend in treatment of GI cancers is toward multimodality treatment. However, there is an increased risk of toxicity when combining modalities such as radiotherapy, chemotherapy, and surgery, thus placing an even greater emphasis or normal-tissue toxicities. Improvements in radiation treatment techniques over the past few decades have allowed dose escalation with improved normal-tissue sparing. The driving force behind improving treatment conformity is the significant short- and long-term morbidity of normal tissue toxicity during and after radiation treatment. The degree of normal-tissue sparing within individuals undergoing radiation treatment is highly variable and depends on tumor type and region. Tumors of the esophagus, for example, are surrounded by lung and spinal cord, while anal cancers are in close proximity to the bladder and rectum. Each subsite of the GI tract requires different techniques and approaches to maximize normal-organ sparing while delivering adequate amounts of radiation to the tumor. The physical properties of proton radiation may offer a distinct benefit in treating GI malignancies.

SY9-5 - Optimization of Anti-Angiogenic Therapy for Gastrointestinal Cancer

ABSTRACT Bevacizumab (BV) was associated with a survival benefit when combined with chemotherapy in metastatic colorectal cancer (mCRC). Patients who received BV plus standard chemotherapy (FOLFOX/XELOX or FOLFIRI/XELIRI) as the initial treatment of mCRC and were then continued on BV with a different chemotherapy regimen as a second-line agent after their cancer progressed lived significantly longer than patients who received chemotherapy alone in the second-line setting, based on the recent results of the ML18147 study. This is the first trial to confirm the efficacy of continuing on a BV-based regimen after disease progression and to prove the necessity of BV continuation for blocking VEGF. Aflibercept, which is a soluble fusion protein consisting of the extracellular domains of human VEGFR-1,2 linked to a human IgG1 Fc portion, binds all VEGF-A isoforms, VEGF-B, and PlGF. Regorafenib is an oral multi-kinase inhibitor that targets VEGFR, PDGFR and KIT kinases. Both drugs showed survival benefit in other phase III trials. Understanding the underlying mechanisms of resistance to anti-angiogenic therapy will facilitate the optimization of the use of these three active agents in the treatment of mCRC. The global phase III AVAGAST trial did not demonstrate a survival benefit of BV when it was administered with a chemotherapy regimen of capecitabine plus cisplatin (XP) for metastatic gastric cancer. Low tumor neuropilin-1 expression was associated with shorter overall survival (OS) in placebo-treated patients. The addition of BV seems to produce a survival benefit; patients with low tumor neuropilin-1 expression had OS treatment hazard ratio values that were better than those with high neuropilin-1 expression. A similar effect was observed in the NO16966 mCRC study (FOLFOX/XELOX ± BV). In addition, lower baseline plasma VEGF-A was correlated with longer OS. Additional data from the AVAGAST trial revealed different survival outcomes based on the histological and regional subtype of gastric cancer. Although European patients with diffuse type and distal non-diffuse type gastric cancer had the worst prognosis for survival; these individuals were most likely to benefit from the addition of BV to XP. Different approaches to the development of novel agents for each histologic type of gastric cancer treatment are required.

Therapeutic actions of melatonin on gastrointestinal cancer development and progression.

Melatonin exerts a multitude of physiological functions including the regulation of the sleep cycle and circadian rhythm. Although the synthesis of melatonin in the pineal gland is regulated by changes in the light/dark cycle, the release of melatonin in the gastrointestinal tract is related to food consumption. Melatonin regulates antioxidative processes and it improves T-helper cell response by stimulating the production of specific cytokines. Melatonin is directly involved in preventing tumor initiation, promotion, and progression in a variety of cancers of the gastrointestinal tract including colorectal cancer, cholangiocarcinoma, hepatocarcinoma, and pancreatic carcinoma. This paper is a review of the literature regarding melatonin in the gastrointestinal tract and as a potential therapy for gastrointestinal cancers.

Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host.

Induction of Gastrin Expression in Gastrointestinal Cells by Hypoxia or Cobalt Is Independent of Hypoxia-Inducible Factor (HIF)

Gastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporter assay. Exposure to a low oxygen concentration (1%) increased gastrin mRNA concentrations in wild-type AGS cells (AGS) and in AGS cells overexpressing the gastrin receptor (AGS-cholecystokinin receptor 2) by 2.1 ± 0.4- and 4.1 ± 0.3-fold (P < 0.05), respectively. The hypoxia mimetic, cobalt chloride (300 μM), increased gastrin promoter activity in AGS cells by 2.4 ± 0.3-fold (P < 0.05), and in AGS-cholecystokinin receptor 2 cells by 4.0 ± 0.3-fold (P < 0.05), respectively. The observations that either deletion from the gastrin promoter of the putative binding sites for the transcription factor hypoxia-inducible factor 1 (HIF-1) or knockdown of either the HIF-1α or HIF-1β subunit did not affect gastrin promoter inducibility under hypoxia indicated that the hypoxic activation of the gastrin gene is likely HIF independent. Mutational analysis of previously identified Sp1 regulatory elements in the gastrin promoter also failed to abrogate the induction of promoter activity by hypoxia. The observations that hypoxia up-regulates the gastrin gene in AGS cells by HIF-independent mechanisms, and that this effect is enhanced by the presence of gastrin receptors, provide potential targets for gastrointestinal cancer therapy.

Su1542 Underuse of Surgical Therapy of Gastrointestinal Cancer in the United States

Su1542 Underuse of Surgical Therapy of Gastrointestinal Cancer in the United States

MicroRNAs and Chronic Inflammation Contribution to Gastrointestinal Integrity

Recent studies have revealed that chronic inflammation represents a major basis for different forms of human malignancies. Chronic inflammations are involved in the pathogenesis of 15-25% of human malignancies. Gastrointestinal (GI) cancer is one of the most common causes of mortality in the European Union. The mechanisms leading to cancer development and its progression are not completely understood. Advances are required both in early detection and therapy of GI cancers. There are many factors connecting inflammation and cancer. Cytokines that are small protein molecules regulating growth, differentiation, development and immune response mechanisms in cells. Overexpression of cyclooxynenase-2 is associated with decreased apoptosis, cell to cell adhesion, increased proliferation and angiogenesis contributes to the increased immunosuppresion and mediates carcinogenetic effects. MicroRNAs are regarded as a novel class of gene expression regulators. They are gene-silencing RNAs which negatively regulate gene expression. After binding to target mRNAs they lead either to mRNA destruction or inhibition of translation. Hence, they can play an important role in carcinogenesis. Currently, almost all of the miRNA-related studies on cancers based on the different expression profile of miRNAs in cancer cells compared to normal cells. In summary, miRNAs, proinflammatory cytokines and other factors, may be involved in cancer development based on chronic inflammation by controlling cell differentiation and apoptosis. Assessing the role of miRNAs will provide the new insights on their contribution to the link between chronic inflammation and subsequent cancer, and new markers for cancer diagnoses and cancer therapy.

Recent advances in targeted endoscopic imaging: Early detection of gastrointestinal neoplasms

Molecular imaging has emerged as a new discipline in gastrointestinal endoscopy. This technology encompasses modalities that can visualize disease-specific morphological or functional tissue changes based on the molecular signature of individual cells. Molecular imaging has several advantages including minimal damage to tissues, repetitive visualization, and utility for conducting quantitative analyses. Advancements in basic science coupled with endoscopy have made early detection of gastrointestinal cancer possible. Molecular imaging during gastrointestinal endoscopy requires the development of safe biomarkers and exogenous probes to detect molecular changes in cells with high specificity anda high signal-to-background ratio. Additionally, a high-resolution endoscope with an accurate wide-field viewing capability must be developed. Targeted endoscopic imaging is expected to improve early diagnosis and individual therapy of gastrointestinal cancer.

Recent developments in therapy for gastrointestinal cancers

Recent developments in therapy for gastrointestinal cancers

Molecular targeted therapy in gastrointestinal cancer

Gastrointestinal cancer is one of the highly prevalent malignant diseases worldwide which is a major cause of morbidity and mortality. Gastric cancer is the second leading cause of cancer mortality in the world and its management, especially in advanced stages, has evolved relatively little[1]. Colorectal cancer (CRC) remains the third most common malignancy and the third leading cause of cancer death worldwide[2]. The surgical treatment is still the most effective therapy for the gastrointestinal cancer. However, the majority of the patients had lost the opporunity of surgical therapy when it was detected at advanced stage, so to seek means other than surgical treatment of gastrointestinal cancer metastasis and recurrence also has an important significance. With the deeping research of the molecular biology, molecular targeted therapy has become the hotspot and focus of comprehensive treatment of gastrointestinal cancer which is proposed against the molecular biological targets such as tumor cell growth, apoptosis, cell cycle, invasion and angiogenesis. Molecular targeted therapy can be grouped into six main areas: the epidermal growth factor receptor (EGFR) inhibitors, anti-angiogenic factors, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinase inhibitors, cyclooxygenase inhibitors. The review of the progress are as follows.