Gastrointestinal Cancer Metastasis Research Articles

The Integrative Analysis of Thrombospondin Family Genes in Pan-Cancer Reveals that THBS2 Facilitates Gastrointestinal Cancer Metastasis.

Recent cancer studies have found that the thrombospondin (THBS) family, including THBS1, THBS2, THBS3, THBS4, and THBS5, play vital roles in the development and progression of human cancers. However, their relationships with tumor stage, prognosis, and tumor immunity in pan-cancer have not been systematically reported. In the present study, we employed versatile public databases to assess the expression and mutations of different THBSs in pan-cancer and performed functional experiments to analyze the roles of THBS2 in gastrointestinal cancer metastasis. Our findings indicate that THBS genes are frequently mutated in various cancers and the dysregulation of THBS family members is associated with the progression of some cancers such as gastric cancer, colon cancer, and lung cancer. Further analyses indicate that THBS genes are associated with cancer hallmarks such as cell cycle and epithelial-mesenchymal transition (EMT). Importantly, thrombospondins, especially THBS1 and THBS2, are correlated with the immune cell infiltration level in gastrointestinal cancers. Our experiments further verified that THBS2 participates in tumor metastasis by enhancing EMT. Therefore, the overall analyses reveal that THBSs might offer us potential chances for tumor diagnosis and therapy.

Strategies of chemotherapy for peritoneal metastasis of gastrointestinal cancer

Peritoneal metastasis of gastrointestinal cancer is an independent factor that seriously affects the prognosis of patients. The "seed-soil" theory is considered to be the main theory to explain peritoneal metastasis. Because of the small size of peritoneal metastatic nodules at the initial stage, early diagnosis is particularly difficult, therefore, the risk assessment of peritoneal metastasis is very important. Recently, the diagnosis methods have gradually developed from clinicopathological factors to cytology and molecular level. In addition, the integrated assessment of multiple groups including radiomics further enriches the accurate diagnosis of peritoneal metastasis. Peritoneal metastasis is a big challenge in the treatment of gastrointestinal cancer which may also lead to refractory malignant ascites, intestinal obstruction, cachexia and other related complications. At present, the treatment is based on systemic chemotherapy. The combination of surgery, intraperitoneal chemotherapy and HIPEC is an effective treatment for peritoneal metastasis of gastrointestinal cancer. How to enrich peritoneal metastasis patients with potential benefits, how to determine the timing of conversion surgery, how to further optimize the existing treatment plan, especially how to formulate treatment plan for patients after conversion surgery, call for improved study design and prospective randomized controlled trials. The goal of continuous efforts is to effectively prolong the survival of gastrointestinal cancer trials patients with peritoneal metastasis.

Unusual pleomorphic cells in axillary lymph node

A man in his 60s with a history of superficial gastric cancer and stage IIIB intestinal adenocarcinoma since 2 years, untreated due to systemic symptoms of myelofibrosis, on follow-up CT...

Effect of MMP-13 degraded SPARC on type I collagen and its biomarker potential in colorectal cancer.

717 Background: Increased collagen deposition and remodeling of the extracellular matrix has been shown to play a role in the pathology of gastrointestinal cancer (GC). The matricellular protein SPARC (secreted proteome acidic and rich in cysteine) binds collagens and hereby regulates collagen fibrillogenesis. Matrix metalloproteinase (MMP) mediated cleavage of SPARC, increases the affinity for collagens up to 20-fold. SPARC has been shown to be overexpressed in GC patients and associated with GC cell invasion and metastasis. Increased expression and cleavage of SPARC might therefore be implicated in GC pathology by increasing collagen deposition. Here, we present the development and validation of a competitive enzyme-linked immunosorbent assay (ELISA) quantifying a specific MMP-13 generated fragment of SPARC - a cleavage site involved in increased collagen affinity. The biomarker potential of this fragment was examined in serum from colorectal cancer (CRC) patients and healthy controls. Moreover, we evaluated the ability of cleaved SPARC to prevent type I collagen degradation in vitro. Methods: A monoclonal antibody was raised against a MMP-13-generated neo-epitope of SPARC and a competitive ELISA assay (SPARC-M) was developed and technically validated. Serum levels were assessed in CRC patients (n=50) and healthy controls (n=30). The ability of cleaved SPARC to prevent collagen degradation was investigated using an ELISA assay measuring type I collagen degradation by MMP-9. Results: SPARC-M was technically robust and specific for SPARC cleaved by MMP-13. The fragment was elevated in CRC patients when compared to healthy controls (p=0.0097). When MMP-13 degraded SPARC was incubated with type I collagen and MMP-9, type I collagen degradation was completely inhibited suggesting that SPARC increases collagen deposition by preventing collagen degradation. Conclusions: SPARC-M was significantly elevated in CRC patients compared to healthy controls suggesting biomarker potential. Biologically, cleaved SPARC may prevent type I collagen degradation hereby leading to a pro-tumorigenic environment. Larger clinical studies are needed to validate the clinical use of this biomarker in GC.

S100A4-MYH9 Axis Promote Migration and Invasion of Gastric Cancer Cells by Inducing TGF-β-Mediated Epithelial-Mesenchymal Transition.

Driver genes conducing to peritoneal metastasis in advanced gastric cancer remain to be clarified. S100A4 is suggested to evolve in metastasis of gastrointestinal cancer, we aim to explore the role of S100A4 plays in metastasis of advanced gastric cancer and the potential mechanism. Transfection of siRNA or cDNA was applied to alter the expression of protein S100A4 and MYH9, investigation of the expression of epithelial and mesenchymal transition (EMT) associated markers was followed. Cell migration assay was used to screen the alteration of migration ability regulated by S100A4 and MYH9. IHC analysis for tissue sample microarray was performed to reveal their relationship with clinical pathological parameters and potential capacity of predicting survival. Consistent overexpression of S100A4 and MYH9 were found in peritoneal metastasis and primary site compared with adjacent normal tissue. Low expression of S100A4 led to increased epithelial markers as wells as decline of mesenchymal makers, while overexpression of S100A4 led to inverse impact. S100A4 expression was closely correlated with increased migration ability and EMT process induced by TGF-β stimulation. Interference of S100A4 led to downregulation of MYH9 and inactivation of Smad pathway through participating in EMT process, which could be reversed by overexpression of MYH9. Moreover, co-expression of S100A4 and MYH9 was identified in tissue microarray and confirmed by immunofluorescence assay. In conclusion, overexpression of S100A4 and downstream molecular MYH9 in advanced gastric cancer predicted poor prognosis; oncogene S100A4 facilitate EMT process induced by TGF-β stimulation, suggesting a potential target in management of peritoneal metastasis of gastric cancer.

Role of FoxM1 in the Progression and Epithelial to Mesenchymal Transition of Gastrointestinal Cancer.

Gastrointestinal (GI) cancer, characterized by its leading mortality, is one of the most common cancers worldwide. The underlying mechanisms contributing to epithelial to mesenchymal transition (EMT) and metastasis of GI cancer are poorly understood. It is well known that a great number of transcription factors including FoxM1, KLF4, STAT3 and so forth, are associated with the process of EMT and have also been strongly implicated in the proliferation, migration, and invasion of GI cancer cells. Forkhead box M1 (FoxM1), a transcription factor of the Forkhead family, is strongly positive in GI cancers and can be regarded as an oncogene in GI cancers. A number of studies have reported that FoxM1 is involved in tumorigenesis and promotes cell proliferation, migration, invasion, angiogenesis, EMT and metastasis by targeting downstream genes. In this review, we will focus on highlighting the functions of FoxM1 in tumorigenesis, angiogenesis, invasion and metastasis of GI cancers, pointing out the roles of FoxM1 in GI cancer EMT through crosstalk with TGFβ, Wnt signaling pathways and ncRNA, to better understand the role of FoxM1 in GI cancer, and will discuss recent relevant patents concerning FoxM1 in tumor therapy.

Implants for Cost-Effective and Accessible Treatment of Gynecologic and Gastrointestinal Cancer Metastasis by Local and Sustained Low-Dose Chemotherapy

Abstract 46 Gynecologic and gastrointestinal malignancies are two of the most prevalent cancer types in low and middle- income countries (LMICs), affecting more than 2 million individuals and killing more than 1 million patients annually. These malignancies at an advanced stage metastasize locally but extensively; this spread is a primary cause of morbidity and mortality, affecting 60-80% of patients in LMICs. Localized chemotherapy can benefit survival of patients with such metastases. Localized chemotherapy is, however, essentially unattainable in resource-limited settings, even though many chemotherapy agents are on the WHO list of essential medicines and are currently off patent. This is because of the high cost of, and frequent hospitalizations required under, the current regimen, as well as the morbidity of bolus dosing. Continuous, low-dose chemotherapy via a locally implanted device can address these adoption barriers. Previous attempts to create implants for localized chemotherapy delivery have been hindered by poorly controlled drug release and inhibiting form factors. This work explores the development of a nonresorbable and laparoscopically deployable implant to administer continuous low-dose chemotherapy. The feasibility of chemotherapy using the proposed implant in LMICs is assessed using physician interviews and literature reviews. Tissue-like silicone elastomers are used to create a matrix-type drug delivery implant that minimizes soft tissue irritation and risk of rupture while allowing laparoscopic manipulation. The synthesis and drug release profile of the silicone-based matrix are characterized for small hydrophilic active agents. Configurations allowing implant deployment through laparoscopic instruments are explored. Proof-of-concept controlled release of a hydrophilic small molecule from a lipophilic, tissue-like silicone elastomer that can be scaled to human form factors is thus established. Localized, low-dose chemotherapy delivered via a fully implantable device holds promise to dramatically reduce the cost and resources necessary for treating advanced-stage gynecologic and gastrointestinal malignancies in LMICs, improving cancer patient outcomes in resource-limited settings. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Aikaterini Mantzavinou No relationship to disclose Michael J. Cima Leadership: T2 Biosystems, MicroChips Biotechnologies, Taris BioMedical Stock or Other Ownership: T2 Biosystems, MicroChips Biotechnologies, Taris BioMedical Research Funding: Pfizer Patents, Royalties, Other Intellectual Property: Too many to describe (over 50 patents) Expert Testimony: Apotex Laura Melanie Tanenbaum Patents, Royalties, Other Intellectual Property: System and Method for Sterile Sheathing of a Medical Probe

Clinicopathological Significance of RhoA Expression in Digestive Tract Cancer: A Systematic Review and Meta-Analysis

RhoA protein expression has been reported in different types of cancer. We performed an up-to-date meta-analysis to evaluate the clinicopathological characteristics of RhoA protein expression in patients with gastrointestinal cancer. We searched in several databases, including MEDLINE (PubMed) and China National Knowledge Infrastructure, to identify studies examining the association between RhoA protein and cancer. The quality of the included studies was assessed. Cochrane Collaboration's Software Review Manager 5.3 was utilized to test the heterogeneity, overall effect, and publication bias of the combined studies. The reported odds ratio and 95% confidence interval (CI) were calculated by using fixed and random effects models depending on the heterogeneity of the included studies. A total of 15 studies met the inclusion criteria of the meta-analysis. RhoA expression was significantly higher in gastrointestinal cancer than in normal tissues. RhoA protein expression in digestive system neoplasms was significantly associated with tumor clinical staging, metastatic status and differentiated degree. However, no association with gender was found. RhoA mRNA expression was no associated with clinicopathological significance. Current evidence supports the conclusion that RhoA expression is associated with clinical staging, metastatic status, and differentiated degree in digestive system neoplasms. RhoA expression may play an important role in the carcinogenesis and metastasis of gastrointestinal cancer.

Abstract B074: Tumor-reactive CD4+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy

Abstract Purpose: To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive CD4+ T cells. Experimental Design: Expansion of CD4+ tumor-infiltrating lymphocytes (TIL) and cancer cell lines was performed from gastrointestinal cancer metastases in 5 patients for the study of antitumor immune recognition. Retroviral transduction of genes encoding the class II, major histocompatibility complex, transactivator (CIITA) was used to induce the expression of major histocompatibility complex (MHC) class II in tumor cell lines. Recognition of autologous tumor cell lines by TIL was evaluated by up-regulation of 4-1BB and OX40 by flow cytometry, and/or secretion of IFNg by ELISA. Results: TIL were expanded from metastases, and new tumor cell lines were generated in 5 patients. Retroviral transduction of CIITA in tumor cell lines effectively induced expression of MHC class II in >80% of cells. Autologous tumor recognition was found in CD4+ TIL from 2 of these 5 patients. In a patient with gastric cancer liver metastases, tumor-reactive CD4+OX40+ TIL were cell-sorted from a TIL cell line. These cells up-regulated OX40 in the presence of all 4 autologous cancer cell lines albeit at different levels, but they did not produce IFNg. This recognition was specifically abolished by pan-MHC class II blocking antibodies. CD4+ TIL clones have been isolated and are being further characterised. Interestingly, tumor-reactive CD8+ TIL were previously identified and characterized in this patient. In a second patient with colon cancer abdominal wall metastases, tumor-reactive CD4+OX40+ TIL were cell-sorted from a TIL cell line. These cells were reactive to all 4 autologous cancer cell lines as they up-regulated OX40 and secreted IFNg. Recognition was blocked by anti-HLA-DR blocking antibodies. CD4+ TIL clones have been isolated and are being further characterized. In the near future, we expect to identify the TCR and HLA restriction element for both patients. We will also determine if CD4+ TIL clones have cross-reactivity against allogeneic HLA-matched gastrointestinal tumor cell lines. Conclusions: This study provides a basis for the development of immunotherapy for patients with advanced gastrointestinal malignancies by first establishing the presence of naturally occurring tumor-reactive CD4+ TIL at the molecular level. Citation Format: Sandy Pelletier, Simon Turcotte. Tumor-reactive CD4+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B074.

Abstract A084: Identification of mutation-reactive T cells in patients with gastrointestinal cancers

Abstract New immunotherapeutic advances for common epithelial cancers relies on our ability to stimulate T lymphocytes against specific tumour antigens (Ag). Next-generation sequencing now allows rapid identification of somatic cancer mutations that can lead to the expression of mutated Ag. We hypothesize that gastrointestinal cancer metastases are infiltrated by T cells recognizing tumour mutated Ag. Our aim is to set up an experimental platform to screen for and study the frequency and function of mutation-reactive T cells, while characterizing novel tumour mutated Ag. To do this, we used two cancer cell lines generated from a liver metastasis of a gastric cancer patient. The cell line A was recognized by an autologous CD8+ T cell clone infiltrating the patient's metastasis, restricted by HLA C*0701, while cell line B was not recognized by the same clone despite its expression of the HLA C*0701. The CD8+ T cell clone was not reactive to a large panel of HLA-C*0701 expressing gastrointestinal cancer cell lines, reinforcing the hypothesis that the Ag recognized was unique to the autologous gastric cancer cell line. Exome and transcriptome sequencing was performed to compare the mutated genes differentially expressed by cancer cell line A and B. A total of 27 mutated Ag were selected as candidates: 26 Ag only expressed by cell line A, and one Ag overexpressed by cell line A. To screen for reactivity of the CD8+ T cell clone to mutated Ag, 25 amino acid (aa) mini-genes containing the mutation flanked upstream and downstream by normal aa were synthesised and cloned in tandem into 3 expression plasmids. A control sequence from the MAGE-A12 gene containing an epitope restricted by HLA-C*0701was included in each tandem minigene (TMG) construct. The mRNA from these 3 TMG constructs were in vitro transcribed and electroporated into CD40-activated B cells expressing HLA C*0701, used as antigen presenting cells. Co-culture assays are ongoing, using the CD8+ T cell clones as effectors and T cells transduced with a MAGE-A12-specific TCR as control. For the detection of mutation-reactive T cells, the sensitivity of TMG expression is compared to pulsing mutated peptides on B cells. Taking advantage of the differential recognition of two cancer cell lines by an autologous CD8+ T cell clone, we have established a bioinformatics approach based on next-generation sequencing to obtain a list of candidate mutated Ag and we have designed an experimental system to assess their recognition by T cells. This platform will allow us to study the function of T cells reactive against metastatic gastrointestinal cancers and should lead to the discovery of new tumour Ag. Gaining a better understanding of T cells reactive to gastrointestinal cancers should ultimately contribute to the development of immunotherapies for these common malignancies. Citation Format: Mélissa Mathieu, Sandy Pelletier, David Laperrière, Sylvie Mader, Simon Turcotte. Identification of mutation-reactive T cells in patients with gastrointestinal cancers. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A084.

Novel mechanism for invasion and metastasis involving metabolic enzymes in intractable cancer cells

Cancer metabolism characterizes the malignant behavior of tumors. Pyruvate kinase M2 (PKM2), a key player in maintaining aerobic glycolysis, stimulates tumor growth by controlling the Warburg effect. It has been shown that PKM2 translocates into the nucleus to regulate the transcriptions of numerous down-stream genes, including PDK1 and LDHA. To investigate the significance of PKM2 in epithelial-mesenchymal transition (EMT), a biological process which promotes the metastasis of cancer cells, we induced EMT in gastrointestinal cancer cells using TGFβ and EGF in vitro. After EMT induction, E-cadherin was down-regulated, whereas Vimentin was up-regulated. PKM2 expression was increased at both the transcriptional and the translational level, and PKM2 translocated into the nucleus. Immunohistochemical staining of PKM2 revealed that PKM2 positivity correlated significantly with lymph node metastasis and distant organ metastasis of gastrointestinal cancer. The present results indicate that nuclear PKM2 plays a crucial role in controlling invasion and metastasis.

Highlights of This Issue

Treatment options for triple negative breast cancer (TNBC) patients are limited in scope and effectiveness, particularly in the metastatic setting. Proia and colleagues show that the TNBC phenotype is highly sensitive to the pleiotropic effects of HSP90 inhibition using the investigational drug ganetespib. Ganetespib simultaneously deactivated multiple oncogenic pathways in TNBC cells, suppressed lung metastasis in mouse models, and potentiated the antitumor activity of standard-of-care TNBC chemotherapeutics in vitro and in tumor xenografts. Shrinkage of metastatic lung and lymphatic lesions were observed in patients undergoing ganetespib monotherapy. These findings support the continued exploration of ganetespib for the clinical management of TNBC.Little is known about T-cell responses against advanced epithelial cancers. By establishing new cancer cell lines and expanding tumor-infiltrating lymphocytes from the same patients, Turcotte and colleagues provide evidence at the clonal and molecular level that naturally occurring CD8+ T cells can exhibit tumor specificity against gastrointestinal cancer metastases. This observation represents a rational basis for the development of T cell-based treatments for patients with these malignancies, which will have to take into account the low frequency of tumor-reactive T cells, the absence of shared antigen recognition across allogeneic tumors, and the heterogeneity in antigen expression by tumors.Ductal carcinoma in-situ (DCIS) is the main precursor of invasive breast cancer and accounts for 25–30% of all breast cancers. Only half will progress to invasive disease during a woman's lifetime, but currently there are no markers for predicting which patients might progress. Allen et al demonstrate that tumor-suppressive myoepithelial cells are altered in a subset of DCIS through up-regulation of integrin αϖβ6 and is significantly associated with recurrence and progression. In-vivo and In-vitro expression of αϖβ6 in myoepithelial cells enhances tumor growth and invasion. This suggests that myoepithelial αϖβ6 may be of prognostic importance and help stratify patient care.Antiangiogenic treatments that target pathways other than VEGF have the potential to treat patients who have progressed despite anti-VEGF therapy and to improve outcomes when used in combination with VEGF-directed therapies. Bendell and colleagues describe the phase I clinical evaluation of dalantercept, a receptor fusion protein that inhibits BMP9/BMP10/ALK1 signaling, in adults with advanced solid tumors. Dalantercept exhibited a safety profile distinct from that of VEGF inhibitors and displayed multiple signs of antitumor activity, including a partial response, long-term stable disease, and correlative pharmacodynamic activity assessed by functional imaging. The BMP9/BMP10/ALK1 pathway is a promising target for antiangiogenic cancer therapy.

Tumor-Reactive CD8+ T Cells in Metastatic Gastrointestinal Cancer Refractory to Chemotherapy

To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells. Expansion of CD8(+) tumor-infiltrating lymphocytes (TIL) and cancer cell lines was attempted from gastrointestinal cancer metastases in 16 consecutive patients for the study of antitumor immune recognition. Retroviral transduction of genes encoding T-cell receptors (TCR) was used to define HLA-restriction elements and specific reactivity. TIL were expanded from metastases in all patients, and new tumor cell lines were generated in 5 patients. Autologous tumor recognition without cross-reactivity against allogeneic HLA-matched gastrointestinal tumors was found in CD8(+) TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8(+) TIL was dominated by cytolytic sister clones reactive to 2 out of 4 autologous cancer cell lines restricted by HLA-C*0701. From the same patient, a rare CD8(+) TIL clone with a distinct TCR recognized all four cancer cell lines restricted by HLA-B*4901. In a patient with bile duct cancer, two distinct antitumor cytolytic clones were isolated from a highly polyclonal CD8(+) TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A*0201. In a third patient, CD8(+) TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA haplotype. This study provides a basis for the development of immunotherapy for patients with advanced gastrointestinal malignancies by first establishing the presence of naturally occurring tumor-reactive CD8(+) TIL at the molecular level.

Relationship of TGF‐β1 and Smad7 expression with decreased dendritic cell infiltration in liver gastrointestinal cancer metastasis

Immune responses and their modulation within the liver are critical to the outcome of liver malignancies. In late-stage tumors, secreted TGF-β promotes oncogenic functions and can confer tolerogenicity to some immune cells like DCs. The TGF-β signaling pathway is involved in the control of several biological processes, including immunosurveillance. The aim of the present study was to assess CD1a(+) and CD83(+) DCs and to evaluate the impact of TGF-β pathway on DCs maturation and distribution in the liver metastases from gastric and colorectal tumors. The percentage of CD83(+) DCs in the liver tissue, surrounding metastasis and in the metastasis-free liver was measured by flow cytometry, and TGF-β levels were assessed in the tissue supernatant from the peritumoral liver after mononuclear cell isolation and in the sera of the same patients. CD1a(+) and CD83(+) DCs were observed in the tumor stroma and border. Out of 73 patients, there was cytoplasmic reactivity: of TGF-β1 in 37 (50.7%); of Smad4 in 62 (84.9%); of Smad7 in 46 (63%), and of TGFβRII in 39 (53.4%) of the metastases. The TGF-β1 expression in tumor cell cytoplasm correlated with low CD1a(+) and low CD83(+) DCs infiltration. The tissue levels of TGF-β1, measured by ELISA in the supernatant were significantly increased in metastases than in normal liver. Using a two-color FACS analysis, we found that the percentage of HLA-DR(+) CD83(+) DCs in metastases was significantly decreased as compared with metastasis-free liver tissue. In conclusion, the positive and negative correlations between the mediators from the TGF-β pathway implied the existence of imbalance and suppression of this cytokine activity. The presence of increased TGF-β expression by immunohistochemistry in tumor cells was confirmed by detection of increased TGF-β tissue level in the supernatant from the tissue homogenate. The observation of low numbers of CD1a(+) and CD83(+) DCs in tumor stroma correlated with TGF-β overexpression in tumor cells, a fact that well documents the immunosuppressive role of TGF-β in metastasis development. The increased percentage of CD83(+) DCs in the peritumoral tissue supposes that there could be active recruitment or local differentiation of DCs in the metastasis border, but inside the tumor the immune cells recruitment and activity are suppressed by TGF-β and by other cytokines.

Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy

Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3(+) T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8(+) cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ~50 × 10(9) T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3(+)CD8(+) cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I-mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I-mediated up-regulation of CD137 (4-1BB) expression on CD8(+) cells suggested that 0-3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.

The role of neural-related factors in the metastasis of the gastrointestinal cancer

Neurotransmitters are identified to be endogenous chemicals and act on neurons to transmit signals to each other or to a target cell across synapse. They are involved in many brain functions including analgesia, reward, food intake, metabolism, reproduction, social behaviors, learning, and memory. Recently, sympathetic nerve fibers were detected in many solid tumors including gastrointestinal cancer, supporting the idea that neural system has effects on tumor progression. Neurotransmitters were secreted from the sympathetic nerve fibers and subsequently infiltrated into tumor tissues. Further studies disclosed the different mechanisms of various kinds of neurotransmitters in the progression of carcinogenesis, including tumor cell proliferation, angiogenesis, and tumor invasion and metastasis. Neurotransmitters are mainly subdivided into four types, amino acids, monoamines, peptides, and others, each of which contains multiple chemicals. For this reason, we cannot describe each in detail. In this review, we will focus on several important neurotransmitters including tachykinis, neuropeptide Y, and b-adrenergic receptors. How they function and their crosstalks with the immune system in the progression, especially the metastasis of gastrointestinal cancer, will be described. Finally, we will summarize the clinical implications in the treatment of gastrointestinal cancer.

Role of Toll-like receptors in microbiota-associated gastrointestinal cancer metastasis

Toll-like receptors (TLRs) serve as specific pattern recognition molecules that bind to microbial components to activate innate immunity and instruct and modulate adaptive immunity in the face of immunological danger. Accumulating evidence supports that TLR signaling pathway responses to luminal microbes participate in the development of gastrointestinal malignancies. This review summarizes current knowledge on the roles of TLR in microbiota-associated gastrointestinal cancer metastasis, focusing on TLR recognition of microbiota ligands, initiating inflammation, and promoting tumorigenesis, as well as the therapeutic strategies to target TLR. Studying the link between TLR signaling and gastrointestinal malignancies offers the possibility to identify novel ways to both prevent and treat gastrointestinal cancer.

Gastrointestinal Cancer Metastasis

It is well acknowledged that the poor prognosis of gastrointestinal cancer is largely due to metastasis, which is the biological hallmark of malignant tumors. Metastasis is considered to be a multistep process in which malignant tumor cells spread inconsecutively from original site to distant organs. As for cancers of gastrointestinal tract, the common target site for metastasis is liver, lymph nodes, peritoneal, and, subsequently, lung and other sites of the body, which in single or as a whole, is the major cause of gastrointestinal cancer-related deaths. Therefore, the early diagnosis and effective treatment of gastrointestinal cancer metastasis is of vital importance, which may lead to substantial elongation of life expectancy of gastrointestinal cancer patients. In order to make further progressions in early diagnosis and intervention, the following three directions should be put due emphases on in future research. Firstly, the cellular and molecular mechanisms of gastrointestinal cancer metastasis should be clarified, such as the mechanisms of local angiogenesis, the heterogeneity of cancer cells, the cross-talk and cascade of signaling transduction systems, the decreased expression of cell adhesion molecules such as E-cadherin, and so on. To elucidate these mechanisms and to block relevant molecular pathways provides the most promising perspectives in the fight against gastrointestinal caner metastasis. And additionally, there are several interesting and enlightening hot points: the relationship between stromal microenvironment and metastatic destination; the role of cancer stem cells in metastasis; and how malignant cells get metastasis ability, inherent or acquired? The second direction is to find out specific and sensible biomarkers of gastrointestinal cancer metastasis and to predict the potential metastasis, to facilitate early diagnosis, which is up to now mainly dependent on insensitive and costly radiographic examinations. And the third one is the optimization of comprehensive treatment including surgical intervention. In this special issue, eight articles on gastrointestinal cancer metastasis are presented. One article discussed the advantages and disadvantages of repeated liver resection in patients with recurrent colorectal liver metastasis. One article reported that N-desulfated heparin is capable of suppressing the metastasis of gastric cancer through inhibiting tumor bFGF expression and tumor angiogenesis with no obvious anticoagulant activity. Yet another article is on the relevance between dietary salt intake and the risk of gastric cancer. The other five articles highlighted four kinds of potential biomarkers for gastrointestinal cancer screening and early diagnosis of metastasis, namely urine-free amino acid, ki-67 antigen, mir-21 and epidermal growth factor receptor (EGFR). J. Fan and his colleagues, through analyzing amino acids in urine samples of gastric cancer patients and healthy volunteers, figured out that urine-free amino acid profiling is of potential value for screening or diagnosing gastric cancer. D. Navarini and his colleagues, from Brazil, reviewed thirty-seven patients who underwent esophagectomy without presurgical chemotherapy or radiotherapy from 2000 to 2010, analyzed the level of EGFR expression and life span, and concluded that EGFR expression is related to higher TNM staging and shorter survival. Despite the obvious advancements made in the research of gastrointestinal cancer metastasis these years, the outcomes are far from final satisfaction, and thus it is still a field that deserves and calls for intensive and thorough research in the future.

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.

Molecular mechanism for hematogenous metastasis of gastrointestinal cancer and its clinical application for therapy

Molecular mechanism for hematogenous metastasis of gastrointestinal cancer and its clinical application for therapy