Therapy For Gastrointestinal Cancers Research Articles

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.

Editorial [Hot Topic: Molecular Targeted Therapy of Gastrointestinal Cancer (Guest Editor: Marcus W. Wiedmann)

Editorial [Hot Topic: Molecular Targeted Therapy of Gastrointestinal Cancer (Guest Editor: Marcus W. Wiedmann)

NOTCH Signaling and ATOH1 in Colorectal Cancers

The Notch receptor signaling pathway regulates expression of the basic helix-loop-helix transcription factor ATOH1 (Math1/Hath1) to determine cell fate in the intestine. In differentiating intestinal stem cells, high levels of Notch activity specify absorptive enterocyte/colonocyte differentiation, whereas high ATOH1 activity specifies secretory (goblet, enteroendocrine, and Paneth) cell differentiation. In colorectal cancer, ATOH1 is a tumor suppressor that is silenced in most tumors, while Notch is oncogenic and often highly active in human tumors. In other gastrointestinal malignancies with features of intestinal metaplasia, such as esophageal and gastric cancers, the Notch-ATOH1 pathway becomes activated. In cancers and preneoplastic tissues that retain the ability to activate ATOH1, therapeutic targeting of this pathway can be achieved by inhibiting Notch activity (with Notch-targeting antibodies or small-molecule inhibitors of γ-secretase). Thus, targeting the Notch-ATOH1 pathway represents a novel approach to differentiation therapy in gastrointestinal cancers.

The potential role of somatostatin analogues in the treatment of gastrointestinal (GI) cancers.

150 Background: Somatostatin receptors (sstr) are expressed in various normal and malignant tissues, including non-neuroendocrine GI solid tumors. Gastric cancer (GC) cells mainly express sstr2 and sstr5, colorectal cancer (CRC) cells predominantly express sstr1 followed by sstr5 and sstr2, and hepatocellular carcinoma (HCC) cells express mainly sstr5 as well as sstr1,2,3. Somatostatin analogues (SAs) may have direct and indirect antitumor activity. Octreotide and lanreotide primarily target sstr2, whereas the new agent pasireotide has high affinity for sstr1,2,3 and sstr5. Methods: Published data evaluating the antitumor properties of SAs in GI tumors were reviewed. Results: The table lists the results of clinical studies in which SAs were evaluated as antitumor therapies in GI cancers. Conclusions: Although octreotide and lanreotide are efficacious in the treatment of symptoms of neuroendocrine tumors, these agents have demonstrated mixed results in the antitumor treatment of non-neuroendocrine GI tumors. Data suggesting potential favorable outcomes with SAs alone or in combination with other agents have been seen in solid tumors with predominant sstr2 expression such as GC. Novel SAs such as pasireotide may have improved antitumor effects in non-neuroendocrine solid tumors expressing multiple sstr compared with octreotide and lanreotide. [Table: see text] [Table: see text]

Insulin‐like growth factor‐I receptor blockade reduces tumor angiogenesis and enhances the effects of bevacizumab for a human gastric cancer cell line, MKN45

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal cancers. The authors previously reported the success of therapy for gastrointestinal cancers using adenoviruses that expressed dominant-negative IGF-IR (IGF-IR/dn). In addition, it has been demonstrated that IGF-IR signaling affects vascular endothelial growth factor (VEGF) expression in some other types of tumors. The objective of the current study was to evaluate this interaction by studying the roles of IGF-IR in tumor angiogenesis and lymphangiogenesis and their implications for targeted therapy in gastric cancer. The impact of IGF signals on the expression of VEGF-A and VEGF-C in a human gastric cancer cell, MKN45, and vascular formation were assessed. The effects of IGF-IR/dn with or without bevacizumab on angiogenesis, lymphangiogenesis, and tumor suppression in mouse xenografts were assessed. IGFs induced the expression of VEGF ligands and up-regulated in vitro vascular vessel formation. IGF-IR/dn reduced VEGF expression, reduced the activation of both protein kinase B (Akt) and mitogen-activated protein kinase (MAPK), and reduced vascular formation, indicating that IGF-IR/dn inhibited tumor growth in mice by inhibiting both angiogenesis and lymphangiogenesis. However, IGF-IR/dn did not affect either blood sugar or body weight in these mice. The combination of IGF-IR/dn and bevacizumab was highly effective against these xenograft tumors, and only this combination resulted in the complete regression of 43% of tumors, reduced the expression of VEGF, and induced apoptosis. The current results indicated that IGF-IR is involved in angiogenesis and lymphangiogenesis through the modulation of VEGF ligand expression in the gastric cancer cell line MKN45. Targeting IGF-IR in combination with agents that block the VEGF pathway may have therapeutic utility for gastric cancer therapy.

BRAF Mutations and their Implications in Molecular Targeting Therapies for Gastrointestinal Cancers

The epidermal growth factor receptor (EGFR) has become an important therapeutic target in gastrointestinal cancers, especially in colorectal cancer. Stimulation of the EGFR activates at least five intracellular signal cascades such as RAS/RAF/MEK(mitogen-activated ERK activating kinase)/ERK(extracellular signal-regulated kinase), PI3K (phosphatidylinositol 3-kinase) /PTEN (phosphatase and tensin homolog)/AKT(v-akt murine thymoma viral oncogene homolog), STAT (signal transducer and activator of transcription), pospholipase C, and SRC/FAK(focal adhesion kinase). These either phosphorylate their target proteins in the cytoplasm or transmit signals from growth factor receptor to the nucleus, thereby initiating subsequent expression of genes that regulate cell proliferation, differentiation, angiogenesis, and survival [1] Recently, monoclonal antibodies have been developed to target EGFR and to inhibit subsequent cellular responses. They include anti-EGFR antibodies such as cetuximab (a chimeric monoclonal immunoglobulin G1 antibody), panitumumab (a fully human monoclonal immunoglobulin G2 antibody), and trastuzumab (a monoclonal antibody against human epidermal growth factor receptor-2 (HER2) as well as inhibitors of tyrosine kinase (TK) domain of EGFR or subsequent molecules such as gefitinib, erlotinib (both inhibitors of EGFR-TK), lapatinib (a dual inhibitor of HER2-TK and EGFR-TK), sunitinib (an inhibitor of the TK of various kinds of proteins), and sorafenib (an inhibitor of RAF, a downstream molecular of RAS). Among these, cetuximab, panitumumab, and trastuzumab have received the most intensive focus of research, and their efficacy has been clearly demonstrated -especially in gastric and colorectal cancer. However, it is also a fact that this efficacy is sometimes modest as objective response rates comprise at best 50% by adding trastuzumab to chemotherapy -even among HER-2 positive gastric cancer patients [2], or between 8 and 11% by cetuximab [3,4] or pamitumumab [5,6] monotherapy in colorectal cancer patients. The efficacy is thus presumed to be restricted to a certain segment of patients. Therefore, identification of predictive markers of response and resistance in performing the EGFR targeting therapies is urgently needed to stratify those patients benefiting most from them. This in turn obviate unnecessary or futile treatment and reduce health care costs, ultimately allowing treatment to be individualized.

Abstract 3476: Combined blockade of IGF-I receptor and VEGF for gastric cancer

Abstract Background Insulin-like growth factor-I receptor (IGF-IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal (GI) cancers. We have shown successful therapy for GI cancers using adenoviruses expressing dominant negative IGF-IR (IGF-IR/dn). On the other hand, IGF-IR signaling affects on vascular endotherial growh factor (VEGF) expression in some tumors. Here, we sought to evaluate the roles of IGF-IR on tumor angiogenesis and lymphangiogenesis and to develop targeting therapy for gastric cancer. Methods The impact of IGF signals on VEGF-A/C expression in gastric cancer cell was assessed. The effects of IGF-IR/dn alone and with bevacizumab on angiogenesis / lymphangiogenesis in mouse xenogfarts were assessed. Results IGFs induced expressions of VEGFs and up-regulated in vitro vascular vessel formation. IGF-IR/dn reduced those expressions and vascular formation. IGF-IR/dn down-regulated tumor size on mice via inhibiting both angiogenesis and lymphangiogenesis. The combination of IGF-IR/dn and bevacizumab was highly effective against tumors on mice. This combination reduced the expression of VEGF and induced apoptosis in the murine tumors most of all. Conclusions IGF-IR is involved in angiogenesis and lymphangiogenesis in gastric cancer. Targeting IGF-IR alone and with blocking VEGF may have therapeutic utility of prevention for gastric cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3476.

Current use and potential role of bevacizumab in the treatment of gastrointestinal cancers

Angiogenesis is essential for cancer growth and metastasis. Vascular endothelial growth factor (VEGF) is a key modulator of angiogenesis. In addition, overexpression of VEGF is correlated with advanced disease and poor prognosis. Bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, is the first anti-angiogenic agent approved by Food and Drug Administration for use in treatment of human solid cancers. Although bevacizumab has received most attention for first-line treatment of advanced colorectal and nonsmall-cell lung cancer, there is a rapidly growing body of evidence for its efficacy in treatment of a number of other solid tumors. We present the current status and potential use of bevacizumab therapy in gastrointestinal cancers.

Technik der Peritonektomie sowie der hyperthermen intraperitonealen Chemotherapie

The treatment of peritoneal carcinomatosis represents a challenge in the therapy for gastrointestinal cancer. A multimodal approach with complete surgical cytoreduction and hyperthermic intraperitoneal chemotherapy can improve the prognosis in selected patients. Complete surgical cytoreduction, consisting of parietal and visceral peritonectomy, is a sophisticated procedure, frequently requiring multivisceral resections and should only be performed by experienced visceral surgeons. In addition, hyperthermic intraperitoneal chemotherapy is of some complexity. Furthermore, regarding the learning curve for this procedure, combined treatment should only be performed in specialised centres. Under optimal conditions, the therapy can be carried out with reasonable morbidity and mortality rates. Patients with peritoneal carcinomatosis should be evaluated by an interdisciplinary team concerning this multimodal therapy option and, if applicable, they should be referred to therapy within the framework of clinical studies.

Role of intensity-modulated radiation therapy in gastrointestinal cancer

Intensity-modulated radiation therapy (IMRT) represents a powerful advance in the planning and delivery of radiation therapy owing to its ability to deliver highly conformal treatment doses while sparing normal tissues. Dosimetric studies have shown the feasibility and theoretical benefit of treating with IMRT over 3D-conformal radiation therapy in gastrointestinal malignancies. Early clinical experience with IMRT in the treatment of gastric, pancreatic, rectal and anal cancers corroborates the dosimetric analyses, with some series reporting lower normal tissue toxicities. This article reviews the radiobiological, physical, technical and clinical aspects of IMRT for gastric, pancreatic, rectal and anal cancer, and summarizes the dosimetric and outcome studies to date.

Targeting apoptosis as an approach for gastrointestinal cancer therapy

Cancers in the gastrointestinal system account for a large proportion of malignancies and cancer-related deaths with gastric cancer and colorectal cancer being the most common ones. For those patients in whom surgical resection is not possible, other therapeutic approaches are necessary. Disordered apoptosis has been linked to cancer development and treatment resistance. Apoptosis occurs via extrinsic or intrinsic signaling each triggered and regulated by many different molecular pathways. In recent years, the selective induction of apoptosis in tumor cells has been increasingly recognized as a promising approach for cancer therapy. A detailed understanding of the molecular pathways involved in the regulation of apoptosis is essential for developing novel effective therapeutic approaches. Apoptosis can be induced by many different approaches including activating cell surface death receptors (for example, Fas, TRAIL and TNF receptors), inhibiting cell survival signaling (such as EGFR, MAPK and PI3K), altering apoptosis threshold by modulating pro-apoptotic and anti-apoptotic members of the Bcl-2 family, down-regulating anti-apoptosis proteins (such as XIAP, survivin and c-IAP2), and using other pro-apoptotic agents. In this review, the authors reviewed the currently reported apoptosis-targeting approaches in gastrointestinal cancers.

Proteomic and metabolic prediction of response to therapy in gastrointestinal cancers

Despite substantial improvements in the diagnosis and treatment of many gastrointestinal cancers, particularly colorectal cancer, numerous patients are only diagnosed in advanced stages of disease, which can preclude curative treatment. Screening and early diagnosis of high-risk individuals might be the most promising approach to improve prognosis; however, molecular biomarkers for early diagnosis of most gastrointestinal cancers are not yet available. The prognosis of patients with advanced gastrointestinal cancers has improved through the development of multimodal treatments and the introduction of targeted therapies. Nonetheless, not all patients benefit equally from these treatment approaches, and toxicity can be substantial. The ability to predict whether a patient will respond to therapy early in their treatment for gastrointestinal cancer may be of particular value to stratify and individualize patient treatment strategies. Despite improvement in the understanding of cancer pathogenesis and progression at the molecular level, the molecular changes that underlie treatment response and/or drug resistance are still largely unknown. PET is the first technique to show promise in prediction of response to therapy, and has resulted in promising advancements, particularly in esophageal and gastric cancers. Tissue-based and blood-based molecular biomarkers are still subject to validation. Prediction of response to treatment could ultimately lead to an overall improvement in prognosis.

Antiangiogenic therapy for gastrointestinal tumors

Angiogenesis plays a major role in the pathogenesis of many disorders. Vascular endothelial growth factor has been shown to be the key regulator of normal and pathological angiogenesis. Increased expression of VEGF has been associated with tumor neovascularization, metastasis and proliferation of cancer cells. Bevacizumab, a monoclonal antibody against VEGF, has shown promising preclinical and clinical activity against different types of cancer, particularly in combination with chemotherapy. There is an increasing evidence that bevacizumab has a disease-modifying effect in metastatic colorectal carcinoma (CRC), and also in advanced hepatocellular carcinoma. Further investigation is needed to evaluate the role of antiangiogenic therapeutic strategies in other gastrointestinal malignancies. This review summarizes recent knowledge about antiangiogenic therapy for gastrointestinal cancers.

Drug Insight: antiangiogenic therapies for gastrointestinal cancers—focus on monoclonal antibodies

Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy-namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4-Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.