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BACKGROUND/AIMS: Many questions in cancer biology remain unanswered. Perhaps the most important issues remaining to be addressed focus on the molecular basis of carcinogenesis. Today's cancer focus lies on genetics and gene expression, which is unlikely to explain the true cause of most cancers or lead to a cure. METHODS: Earlier, we provided a plausible mechanism for this process, specifically, that most cancers develop in response to pathogenic stimuli that induce chronic inflammation, fibrosis, and remodeling of the cellular microenvironment. Collectively, these changes generate a precancerous niche (PCN) in which fibrosis and remodeling are ongoing secondary to persistent inflammation, followed by the deployment of a chronic stress escape strategy (CSES). If the CSES is unsuccessful, the cell undergoes a normal cell to cancer cell transformation (NCCT). RESULTS: Here, we highlight the critical role of fibroblasts as the first cells to undergo neoplastic transformation to a cancerous phenotype which is based on several critical findings. First, persistent disruption of homeostatic crosstalk increases lysyl oxidase activity and lysine oxidation which leads to increased collagen stiffness and decreased elasticity. If unresolved, chronic tissue stress will lead to an escape strategy that involves the recruitment of fibroblasts and fibrocytes from the bone marrow as well as cells undergoing an epithelial-mesenchymal transition (EMT). This yields a heterogeneous pool of cells that express both epithelial and mesenchymal markers and that will ultimately differentiate into cancer-associated fibroblasts (CAFs). Finally, CAFs undergo a mesenchymalepithelial transition (MET) and express epithelial markers that facilitate their integration into the target tissue. CONCLUSION: Here, we review the published findings that led us to this conclusion which is the most plausible answer to this critical question.
Assuntos
Conhecimento , Neoplasias , Humanos , Fibroblastos/metabolismo , Neoplasias/patologia , Transição Epitelial-Mesenquimal/genética , Fibrose , Inflamação/patologia , Linhagem Celular Tumoral , Microambiente Tumoral/genéticaRESUMO
Radioactivity and radiation-induced mutations are believed to be primary causal examples of cancer-initiating events (stimulus). The assumption that an increase in cancer risk develops from any amount of radiation gave rise to the linear no-threshold model. This also led to the assumption that cancer is caused by somatic mutations as described by the somatic mutation theory. Against this backdrop, in actuality only ~5%-10% of cancers result from somatic mutations or its various modifications, while ~80% of cancers are still termed as 'sporadic', meaning that their cause is unknown. Therefore, both the linear no-threshold model and the somatic mutation theory have resulted in an incongruity in thinking. Decades of molecular and clinical research since 2012 led to the development of the cancer paradigm, "Epistemology of the origin of cancer", which explains why the majority of cancers originate as a result of a sixstep sequence of events. An understanding of the essentials of physics helps to explain the interconnections between physics and the biology of cancer. This allows for a much-needed reconciliation of past errors and leads to a deeper understanding of carcinogenesis.
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Conhecimento , Neoplasias , Carcinogênese/genética , Humanos , Mutação , Neoplasias/genética , FísicaRESUMO
Hysteron proteron reverses both temporal and logical order and this syllogism occurs in carcinogenesis and the somatic mutation theory (SMT): the first (somatic mutation) occurs only after the second (onset of cancer) and, therefore, observed somatic mutations in most cancers appear well after the early cues of carcinogenesis are in place. It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers as clinical data show little support for this theory when compared against the metrics of patient outcomes. Ever since the discovery of the double helical structure of DNA, virtually all chronic diseases came to be viewed as causally linked to one degree or another to mutations, even though we now know that genes are not simply blueprints, but rather an assemblage of alphabets that can, under non-genetic influences, be used to assemble a business letter or a work of Shakespearean literature. A minority of all cancers is indeed caused by mutations but the SMT has been applied to all cancers, and even to chemical carcinogenesis, in the absence of hard evidence of causality. Herein, we review the 100 year story of SMT and aspects that show why genes are not just blueprints, how radiation and mutation are associated in a more nuanced view, the proposed risk of cancer and bad luck, and the in vitro and in vivo evidence for a new cancer paradigm. This paradigm is scientifically applicable for the majority of non-heritable cancers and consists of a six-step sequence for the origin of cancer. This new cancer paradigm proclaims that somatic mutations are epiphenomena or later events occurring after carcinogenesis is already underway. This serves not just as a plausible alternative to SMT and explains the origin of the majority of cancers, but also provides opportunities for early interventions and prevention of the onset of cancer as a disease.
Assuntos
Modelos Teóricos , Neoplasias/patologia , Carcinogênese/genética , Transformação Celular Neoplásica , Dano ao DNA/efeitos da radiação , Humanos , Inflamação , Mutação , Neoplasias/genética , Neoplasias/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self-communication (intracrine and autocrine), and adjacent communication with nearby cells (juxtacrine), which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling) or over large distances via hormones (endocrine). The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins), occluding junctions (Tight Junctions), and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes). The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM) via the different transmembrane adhesion proteins (Cadherins and Integrins). We have here reviewed cell-cell communication involving (1) the components of junctions and their dynamic interplay with the other aspects of communication, including (2) the tumor microenvironment and carcinogenesis, (3) coupling and migration, (4) the underlying cell-cell and sub-cellular communication mechanisms (signaling) of anticancer treatments, and finally, (5) aspects of recent research on cell-cell communication.
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Antineoplásicos/uso terapêutico , Carcinogênese , Comunicação Celular , Microambiente Tumoral , HumanosRESUMO
Global economies and their health systems face a huge challenge from cancer: 1 in 3 women and 1 in 2 men will develop cancer in their lifetime. In the less developed countries, the volume of cancer patients will overwhelm the existing healthcare systems. Even in developed regions, patients with upper gastrointestinal (GI) cancer usually present with locally advanced tumors that their prognosis is poor. A detailed knowledge of anatomy, embryology, epidemiology, tumor classifications and tumor growth is key understanding and evaluating the relevant research. We review undervalued criteria necessary to evaluate the response to multimodal therapy for upper GI cancers.
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Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Neoplasias Esofágicas/epidemiologia , Feminino , Humanos , Masculino , Prognóstico , Neoplasias Gástricas/epidemiologiaRESUMO
BACKGROUND: Since the "War on Cancer" was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type. DISCUSSION: Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patient's own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy. SUMMARY: Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer.
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Detecção Precoce de Câncer , Neoplasias/diagnóstico , Neoplasias/terapia , Medicina de Precisão , Protocolos Antineoplásicos , Terapia Combinada , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/tendências , Humanos , Neoplasias/patologia , Medicina de Precisão/métodos , Medicina de Precisão/tendênciasRESUMO
Summary: A 44-year-old athletic man presented in 2009 with severe low back pain. Dual-energy x-ray absorptiometry revealed severe osteoporosis; serum testosterone was 189 ng/dL while serum estradiol (E2) measured by liquid chromatography/mass spectrometry was 8 pg/mL. DNA was extracted and sequenced from a blood sample from the patient since his maternal first cousin also had low bone mass and both patients were screened for aromatase dysfunction by PCR analysis for the CYP19A1 gene, which encodes aromatase. No known pathologic mutations were observed in the coding exons, but novel single nucleotide polymorphisms were detected both in the proband and in his cousin. Treatment with topical testosterone started in August 2010. Over the next 8 years, testosterone dosage was varied and switched from topical gel to injections and maintained on depo-injections of testosterone at about 60 mg once per week. Re-examination in March 2012 included a brain MRI to exclude pituitary lesions; hyperparathyroidism was ruled out (normal serum parathyroid hormone, calcium, and calcium to phosphorous ratio) and celiac disease was excluded (negative transglutaminase antibodies). Follow-up in October 2018 showed improved bone mineral density of the lumbar spine by 29% and of the left femoral hip by 15% compared to baseline measurements. This reveals the importance of measuring serum E2 for making the correct diagnosis, as well as for monitoring a therapeutic effect. Herein, we propose treatment of male osteoporosis where serum E2 levels are below about 20 pg/mL with testosterone to reverse osteoporosis. Learning points: Estrogen deficiency in the diagnosis of male idiopathic osteoporosis. Importance of serum estradiol in male osteoporosis. Role of polymorphisms in aromatase gene on bone health. Reversal of osteoporosis. Tailored testosterone treatment for bone health.
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Tumor involvement of the peritoneum-peritoneal carcinomatosis-is a heterogeneous form of cancer that had been generally regarded as a sign of systemic tumor disease and as a terminal condition. The multimodal treatment approach for patients with peritoneal carcinomatosis, which had been conceived and developed, consists of what is known as cytoreductive surgery, followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Depending on the tumor mass as assessed intraoperatively and the histopathological differentiation, patients who undergo cytoreductive surgery and HIPEC have a significant survival benefit. Mean increases in the survival period ranging from six months to up to four years have now been reported. In view of the substantial logistic effort and the extent of the surgery involved, this treatment approach represents a major challenge both for patients and for surgical oncologists, as well as for the members of the overall interdisciplinary structure required, which includes oncology, anesthesiology and intensive care, psycho-oncology, and patient management. The surgical procedures alone may take 8-14 hr. The present paper provides an overview of the basis for the approach and the use of specialized classifications and quantitative prognostic indicators.
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Antineoplásicos/administração & dosagem , Hipertermia Induzida/métodos , Neoplasias Peritoneais/terapia , Peritônio/cirurgia , Terapia Combinada , Humanos , Injeções Intraperitoneais , Laparoscopia , Neoplasias Peritoneais/mortalidade , PrognósticoRESUMO
Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate-generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and beta-catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study, the influence of PGK1 on CXCR4 and beta-catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study, we found that PGK1 regulates the expression of CXCR4 and beta-catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid-mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness suggesting that, PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and beta-catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum.
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Regulação Neoplásica da Expressão Gênica , Neoplasias Peritoneais/secundário , Fosfoglicerato Quinase/genética , Neoplasias Gástricas/patologia , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Humanos , Imuno-Histoquímica , Modelos Biológicos , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Fosfoglicerato Quinase/metabolismo , Interferência de RNA , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
BACKGROUND/AIMS: Tumor dissemination is frequent in gastric cancer and implies a poor prognosis. Cure is only achievable provided an accurate staging is performed at primary diagnosis. In previous studies we were able to show a relevant impact of increased phosphoglycerate kinase 1 expression (PGK1; a glycolytic enzyme) on invasive properties of gastric cancer in-vivo and in-vitro. Thus the aim of the present study was to evaluate the effect of enhanced PGK1 expression in gastric cancer employing magnetic resonance (MR)-imaging combined with positron emission tomography (PET), a recently emerging new high resolution imaging technique in a mouse model. METHODS: A metastatic nude mouse model simulating human gastric cancer behavior by orthotopic tumor implantation was established. Mice were divided into one control group (n=5) and two experimental groups (n=30) divided by half in animals baring tumors from MKN45-cells and MKN45-cells with plasmid-mediated overexpression of PGK1. In the course of tumor growth MR-imaging and PET/MRI fusion was performed. Successively experimental animals were examined macroscopically and histopathologically regarding growth, metastasis and PGK1 expression. RESULTS: Elevated PGK1 expression increased invasive and metastatic behavior of implanted gastric tumors significantly. MR/PET- imaging results in-vivoand subsequent ex-vivo findings concerning tumor growth and metastasis correlated excellently and could be underlined by concordant immuohistochemical PGK1 staining. CONCLUSION: Consistent in-vivo findings suggest that PGK1 might be crucially involved in gastric malignancy regarding growth and metastasis, which was also underlined by novel imaging techniques. Thus, PGK1 may be exploited as a prognostic marker and/or be of potential therapeutic value preventing malignant dissemination.
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Fosfoglicerato Quinase/metabolismo , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Camundongos , Camundongos Nus , Metástase Neoplásica , Fosfoglicerato Quinase/genética , Tomografia por Emissão de Pósitrons , Prognóstico , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/enzimologiaRESUMO
BACKGROUND: Gastroesophageal reflux is caused by transient lower esophageal sphincter relaxations (TLESRs) in healthy individuals and in most patients with gastroesophageal reflux disease (GERD). Refluxate is normally propelled by pharyngeally induced swallowing events, but TLESRs may also be accompanied by retrograde esophageal motor responses (EMRs). These contractions have not previously been investigated and their effect on esophageal clearance is not known. The aim of this study was to assess the frequency of EMRs after TLESR in healthy individuals and GERD patients and to develop an animal model for further investigation of EMRs. MATERIALS AND METHODS: The frequency of TLESRs and esophageal body contractions after TLESRs was assessed using ambulatory manometry in five healthy individuals and five GERD patients. An animal model was developed for reproducible provocation of TLESRs and subsequent EMRs. RESULTS: Patients with GERD have significantly more TLESRs than healthy individuals. However, post-TLESR EMRs were not more frequent in the GERD group. All post-TLESR EMRs presented as simultaneous contractions of the esophagus. The feline model allowed reproducible initiation of the esophageal motor response after TLESR, showing that EMRs can be induced by external mechanoreceptor stimulation simultaneously with LES relaxation. This experimental design imitates the conditions after fundoplication in humans. CONCLUSIONS: The study demonstrated that GERD patients have significantly more TLESRs in comparison with healthy individuals, but these were only incidental to EMRs. Further research is needed to improve our understanding of esophageal motility disorders. The animal model presented offers a feasible tool for investigating TLESR-induced esophageal motility.
Assuntos
Esfíncter Esofágico Inferior/fisiologia , Refluxo Gastroesofágico/patologia , Atividade Motora/fisiologia , Adulto , Animais , Gatos , Modelos Animais de Doenças , Desenho de Equipamento , Esfíncter Esofágico Inferior/fisiopatologia , Feminino , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Manometria , Relaxamento Muscular/fisiologia , Valores de Referência , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND AND AIM: Pretherapeutic identification of esophageal squamous cell carcinomas (ESCCs) that are likely to respond to neoadjuvant chemoradiotherapy is important in the attempt to improve the prognosis for patients. In the present study, expression of members of the transforming growth factor-beta1 (TGF-beta1) signaling pathway was investigated in pretherapeutic biopsies from 97 ESCCs (cT3, cN0/+, cM0) in patients who underwent neoadjuvant chemoradiotherapy (45 Gy plus cisplatin and 5-fluorouracil) and subsequent esophagectomy in the setting of a single-center prospective treatment trial. MATERIALS AND METHODS: Expression of TGF-beta1 and its downstream effectors Smad4 and Smad7 was assessed using quantitative reverse transcription polymerase chain reaction from RNA prepared from pretherapeutic tumor biopsies. The presence of phosphorylated Smad2 was assessed immunohistochemically. RESULTS: Expression of TGF-beta1 (mean 7.8; range 0.0-25.7 arb. units), Smad4 (mean 0.1; range 0.0-0.4 arb. units), and Smad7 (mean 1.6; range 0.4-16.1 arb. units) varied substantially between the patients. Tumors with total or subtotal regression, as determined by histopathological examination after neoadjuvant chemoradiotherapy, showed significantly higher levels of Smad4 mRNA expression than tumors with minor or no regression (P = 0.032). TGF-beta1 and Smad7 mRNA expression as well as Smad2 protein expression were of no prognostic value. Expression of the four genes under analysis also showed no impact on the overall survival. In contrast, the overall survival correlated significantly with histopathological regression (P < 0.0001) and to a minor degree also with clinical regression grading (P = 0.0254). INTERPRETATION: Among the parameters analyzed, only Smad4 was found to have possible predictive value for esophageal squamous cell carcinoma in patients receiving neoadjuvant chemoradiotherapy.
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Valor Preditivo dos Testes , Transdução de Sinais/genética , Proteína Smad4/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , RNA Mensageiro/análise , Proteína Smad2/metabolismo , Proteína Smad7/genética , Análise de Sobrevida , Fator de Crescimento Transformador beta1/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell-derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell-derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis.
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Gelatinases/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metástase Neoplásica/patologia , Células 3T3 , Animais , Linhagem Celular , Primers do DNA , Gelatinases/genética , Humanos , Rim , Neoplasias Hepáticas/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos , Invasividade Neoplásica , Metástase Neoplásica/genética , RNA Neoplásico/genética , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND/AIMS: Intraperitoneal free cancer cells are associated with a higher risk of recurrence and a poorer prognosis in colorectal surgery. Tumour recurrence may occur early after surgery. One potential mechanism is the ability of peritoneal lesions to attract tumour cells. METHODS: In Wag-Rija rats, the parietal peritoneum was resected on a defined area, a corresponding control area was marked in the same rat and colorectal tumour cells (CC531) were applied into the abdomen after surgery. Tissue was harvested 6 or 9 days after surgery to evaluate intra-abdominal tumour growth. Additionally tumour cells were applied 2 weeks after peritoneal resection to investigate tumour growth in a healed area of peritonectomy. Specimens were evaluated for macroscopic tumour spread, weight of the abdominal wall and maximal tumour thickness. RESULTS: Macroscopic tumour spread, weight of the abdominal wall and maximal tumour thickness were significantly increased within the area of peritonectomy after both 6 and 9 days compared to the control area. However, only macroscopic tumour expansion was significantly increased in the healed area of peritonectomy. CONCLUSION: Peritoneal defects may play an important role in the pathogenesis of tumour implantation and might have some impact on tumour recurrence. The peritoneal damage should be kept as low as possible.
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Neoplasias Colorretais/patologia , Neoplasias Peritoneais/secundário , Peritônio/cirurgia , Animais , Modelos Animais de Doenças , Masculino , Invasividade Neoplásica/patologia , Transplante de Neoplasias , Ratos , Fatores de Tempo , CicatrizaçãoRESUMO
OBJECTIVES: Indoleamine-2,3-Dioxygenase (IDO) is an immunosuppressive molecule inducible in various cells. In addition to classic IDO (IDO1), a new variant, IDO2, has recently been described. When expressed in dendritic cells (DCs) or cancer cells, IDO was thought to suppress the immune response to tumors. A novel therapeutic approach in cancer envisages inhibition of IDO with 1-methyl-tryptophan (1MT). The levo-isoform (L-1MT) blocks IDO1, whereas dextro-1MT (D-1MT), which is used in clinical trials, inhibits IDO2. Here we analyze IDO2 expression in human cancer cells and the impact of both 1-MT isoforms on IDO activity. METHODS: Surgically extirpated human primary tumors as well as human cancer cell lines were tested for IDO1 and IDO2 expression by RT-PCR. IDO1 activity of Hela cells was blocked by transfection with IDO1-specific siRNA and analysed for tryptophan degradation by RP-HPLC. The impact of D-1MT and L-1MT on IDO activity of Hela cells and protein isolates of human colon cancer were studied. RESULTS: Human primary gastric, colon and renal cell carcinomas constitutively expressed both, IDO1 and IDO2 mRNA, whereas cancer cells lines had to be induced to by Interferon-gamma (IFN-gamma). Treatment of Hela cells with IDO1-specific siRNA resulted in complete abrogation of tryptophan degradation. Only L-1MT, and not D-1MT, was able to block IDO activity in IFN-gamma-treated Hela cells as well as in protein isolates of primary human colon cancer. CONCLUSIONS: Although IDO2 is expressed in human tumors, tryptophan degradation is entirely provided by IDO1. Importantly, D-1MT does not inhibit the IDO activity of malignant cells. If ongoing clinical studies show a therapeutic effect of D-1MT, this cannot be attributed to inhibition of IDO in tumor cells.
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Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias/metabolismo , Triptofano/análogos & derivados , Triptofano/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Células HeLa , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/genética , RNA Mensageiro/biossíntese , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estereoisomerismo , Triptofano/química , Triptofano/farmacologiaRESUMO
BACKGROUND: In cancer, a response to therapy implies a reduction in the volume or activity of localized and/or metastatic tumors. In localized upper gastrointestinal cancer, there is no accepted definition of clinical response; however, tumor shrinkage is frequently observed when preoperative therapy is administered. As patients with upper gastrointestinal cancers often undergo multimodal therapy, it is therefore imperative that new definitions for assessing the response to preoperative therapy be established. METHODS: We reviewed the development of response criteria from a historical perspective, with particular emphasis on the criteria used to assess upper gastrointestinal cancers. RESULTS: Observing the response to preoperative therapy appears to make it possible to distinguish between favorable and unfavorable clinical biology in the cancer. Patients who experience a response to preoperative treatment appear to fare better in terms of overall survival than those whose cancers do not respond. We reviewed the published results regarding the response to preoperative therapy and the implications of this for patients. CONCLUSIONS: This review of the literature suggests that a variety of tools are available for defining the response to preoperative therapy and that these need to be exploited. Developing reliable methods of assessing the response will improve the individualization of therapy for patients with gastroesophageal cancer. There is a strong need for surrogate markers for efficacy in order to assess responses that are capable of predicting patient outcome.
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Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Terapia Neoadjuvante , Adenocarcinoma/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Esofagectomia , Humanos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significantly longer survival in patients with peritoneal carcinomatosis (PC). So far, no morphological imaging method has proven to accurately assess the intra-abdominal tumor spread. This study was designed to predict tumor load in patients with PC using dual-modality (18)FDG-PET/CT and to compare the results with those of PET and CT alone by correlating imaging findings with intraoperative staging. METHODS: Twenty-two patients with PC from gastrointestinal (n = 13), ovarian cancer (n = 8), and mesothelioma (n = 1) underwent contrast-enhanced (18)FDG-PET/CT before surgery and HIPEC. In a retrospective analysis PET, CT, and fused PET/CT were separately and blindly reviewed for the extent of peritoneal involvement using the Peritoneal Cancer Index (PCI). Imaging results were correlated with the intraoperative PCI using Pearson's correlation coefficient and linear regression analysis. RESULTS: There was a strong correlation between the PCI obtained with PET/CT and the surgical PCI with respect to the total score (r = 0.951) as well as in the regional analysis (small bowel, r = 0.838; other, r = 0.703). The correlation was slightly lower for CT alone (total score, r = 0.919; small bowel, r = 0.754; other, r = 0.666) and significantly lower (p = 0.002) for PET alone (total score, r = 0.793; small bowel, r = 0.553, other, 0.507). CONCLUSIONS: Contrast-enhanced CT is superior compared with PET alone to predict the extent of PC. In our patient group, the combination of both modalities (contrast enhanced PET/CT) yielded the best results and proved to be a useful tool for selecting candidates for peritonectomy and HIPEC.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Peritoneais/diagnóstico por imagem , Neoplasias Peritoneais/terapia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adulto , Idoso , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Feminino , Fluordesoxiglucose F18 , Humanos , Hipertermia Induzida , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Seleção de Pacientes , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos , Procedimentos Cirúrgicos Operatórios , Carga TumoralRESUMO
Morbid obesity is a recognized risk factor for gastrointestinal cancer. Little is known about pancreatic cancer developing after gastric bypass surgery or about surgery for this type of tumor following bariatric surgery. This report describes a case of pancreatic head cancer identified 3 months after laparoscopic sleeve gastrectomy for morbid obesity. During routine follow-up, mild abdominal pain and elevated pancreatic enzymes prompted computed tomography, which revealed mild edematous pancreatitis. Hyperbilirubinemia developed, and magnetic resonance imaging showed a pancreatic head tumor. CA19-9 was elevated. After a pylorus-preserving pancreatic head resection, the postoperative course was uneventful. The patient received adjuvant chemotherapy. Unfortunately, at the time of writing (9 months postoperatively), a local recurrence and hepatic metastases were diagnosed. Patients treated with bariatric surgery who develop new symptoms or report constant mild symptoms should be evaluated using endoscopy and radiomorphological imaging. Interdisciplinary obesity treatment can then offer significant benefits for the patient, particularly in the case of pancreatic cancer, which is still difficult to diagnose. In addition, there is a need for epidemiological studies of patients who undergo bariatric surgery and subsequently develop cancer.
Assuntos
Carcinoma Ductal Pancreático/cirurgia , Gastrectomia , Laparoscopia , Obesidade Mórbida/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/complicações , Obesidade Mórbida/patologia , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/patologia , PiloroRESUMO
BACKGROUND: The incidence of colorectal carcinoma increases rapidly in aged patients. We investigated retrospectively the differences in treatment relative to the patients' age. PATIENTS AND METHODS: A total of 394 patients with colorectal carcinoma (group I: > or =80 years, n = 197; group II: 60-79 years, n = 197) were analyzed in an average period of 4 years in relation to surgery, comorbidities, postoperative morbidity, mortality, survival and recurrence. RESULTS: Patients > or =80 years had a significantly higher rate of comorbid conditions (p = 0.04; cardiovascular, p = 0.01; diabetes mellitus, p < 0.05) and more carcinomas in the sigmoid/rectum (72% vs. 67%; p < 0.05). Tumor stage, R0 resection rate, and overall complication rate were not influenced by age. The 30-day mortality rate was significantly higher in group I (12% vs. 3%; p = 0.02). Emergency surgical procedures were required significantly more often in group I (14%) than in group II (5%; p = 0.003). The 5-year survival rate among patients in group I was 30.1% compared to 50.5% among patients in group II (p < 0.0001). CONCLUSIONS: Elderly patients have a higher rate of comorbidity and a higher postoperative 30-day mortality rate. Tumor stage, R0 resection rate, and overall postoperative complication rate do not appear to be influenced by age. The higher rate of emergency operations on patients > or =80 years is associated with the higher 30-day mortality. Even in patients aged > or =80 years, attention should focus on the long-term oncological results, after appropriate assessment of the preoperative risk.
Assuntos
Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/mortalidade , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon.