Dissemination Of Colorectal Cancer Research Articles

PDIA3 driven STAT3/PD-1 signaling promotes M2 TAM polarization and aggravates colorectal cancer progression.

This inquiry endeavors to delineate the influence of PDIA3 on tumor-associated macrophages within the realm of colorectal malignancies, whilst elucidating the intrinsic biochemical pathways. Leveraging bioinformatics, we scrutinized the symbiosis between PDIA3, STAT3, and CD274. A xenograft model in immunodeficient murine served to assess PDIA3's impact on colorectal carcinogenesis. Further, Western blot analysis quantified the protein expression of PDIA3, p-STAT3, PD-1, XBP-1, assorted enzymes, and IL-6. Moreover, in vitro assays gauged SW480 cellular dynamics inclusive of migration, invasive potential, and proliferation. Bioinformatics exploration exposed PDIA3's elevated presence in diverse cancers, with a marked expression in colorectal cancer, as per TCGA and GEO repositories. Correlative studies showed PDIA3 positively aligning with STAT3 and CD274, the latter also associated with monocyte-derived macrophages. Comparative analysis of colorectal neoplasms and normal colon samples unveiled heightened levels of PDIA3 markers which, when overexpressed in SW480 cells, escalated tumorigenicity and oncogenic behaviors, with a noted decrease upon PD-1 monoclonal antibody intervention. PDIA3 augments the M2 polarization of tumor-associated macrophages via modulation of the STAT3/PD-1 cascade, thus invigorating the tumorous proliferation and dissemination in colorectal cancer. Such revelations position PDIA3 as an auspicious target for PD-1 blockade therapeutics, offering a promising foundation for rectifying colorectal carcinoma.

Targeting Hyaluronic Acid and Peritoneal Dissemination in Colorectal Cancer

Peritoneal metastasis (PM) from colorectal cancer (CRC) carries a significant mortality rate for patients and treatment is challenging. The development of PM is a multistep process involving detachment, adhesion, invasion and colonization of the peritoneal cavity. Cytoreductive surgery and HIPEC (hyperthermic intraperitoneal chemotherapy) for PM from CRC has some benefit but overall survival is poor and recurrence rates are high. Treatments to prevent the development of peritoneal metastasis could have the potential to improve CRC survival and disease-free outcomes.The ability of cancer cells to invade the peritoneum and become established as metastatic tumors is influenced by a multifactorial process. Hyaluronic acid (HA) has been shown to coat the mesothelial cells of the peritoneum and has been demonstrated to be utilized in various malignancies as part of the metastatic process in peritoneal dissemination. CD44, RHAMM (CD168) and ICAM-1 have all been shown to be binding partners for HA. Targeting HA-mediated binding may prevent adhesion to distant sites within the peritoneum through suppression of interaction of these molecules. Here we review the current literature and discuss key molecules involved with PM dissemination, with the potential to target these mechanisms in the delivery of future treatments.

Stromal Galectin-1 Promotes Colorectal Cancer Cancer-Initiating Cell Features and Disease Dissemination Through SOX9 and β-Catenin: Development of Niche-Based Biomarkers.

Over 90% of colorectal cancer (CRC) patients have mutations in the Wnt/β-catenin pathway, making the development of biomarkers difficult based on this critical oncogenic pathway. Recent studies demonstrate that CRC tumor niche-stromal cells can activate β-catenin in cancer-initiating cells (CICs), leading to disease progression. We therefore sought to elucidate the molecular interactions between stromal and CRC cells for the development of prognostically relevant biomarkers. Assessment of CIC induction and β-catenin activation in CRC cells with two human fibroblast cell-conditioned medium (CM) was performed with subsequent mass spectrometry (MS) analysis to identify the potential paracrine factors. In vitro assessment with the identified factor and in vivo validation using two mouse models of disease dissemination and metastasis was performed. Prediction of additional molecular players with Ingenuity pathway analysis was performed, with subsequent in vitro and translational validation using human CRC tissue microarray and multiple transcriptome databases for analysis. We found that fibroblast-CM significantly enhanced multiple CIC properties including sphere formation, β-catenin activation, and drug resistance in CRC cells. MS identified galectin-1 (Gal-1) to be the secreted factor and Gal-1 alone was sufficient to induce multiple CIC properties in vitro and disease progression in both mouse models. IPA predicted SOX9 to be involved in the Gal-1/β-catenin interactions, which was validated in vitro, with Gal-1 and/or SOX9—particularly Gal-1high/SOX9high samples—significantly correlating with multiple aspects of clinical disease progression. Stromal-secreted Gal-1 promotes CIC-features and disease dissemination in CRC through SOX9 and β-catenin, with Gal-1 and SOX9 having a strong clinical prognostic value.

O17: HYALURONIC ACID DEPENDENT ADHESION IN COLORECTAL CANCER PERITONEAL METASTASIS

Abstract Introduction Peritoneal Metastasis (PM) in Colorectal Cancer (CRC) undoubtedly remains a challenge to treat and often portends a poor prognosis for patients. Hyaluronic acid (HA) is found throughout the body, including coating of the peritoneum. Interaction of HA with HA-dependent adhesion molecules can facilitate cell adhesion within the peritoneum. HA may play a role in spread of PM in CRC in association with known HA-receptor molecules CD44, RHAMM and ICAM-1. Method Expression of HA-dependent and HA-independent adhesion molecules were examined in CRC using tissue microarray datasets and matched to clinicopathological data. In-vitro peritoneal modelling assessed cellular adhesion when treated with a competitive HA-inhibitor (HAi) or excess exogenous HA. An in-vivo Xenograft peritoneal model, using CD1 nude mice injected with CRC cells, were treated with either HAi or excess exogenous HA and compared to a control (PPL: PE9445FC2). Result There is a significant increase in expression of HA-dependent adhesion molecules seen in CD44, RHAMM and ICAM-1 in CRC (p=<0.0001). Whilst Non-HA-dependent adhesion molecules demonstrated either significant downregulation or no expression difference. Cellular adhesion was decreased in three CRC cell lines when treated with HAi or excess HA. Treatment with HAi and HA in-vivo confirmed a significant reduction in PM, compared to controls (HAi p=0.0094, HA p=0.0009). Conclusion HA-dependent adhesion molecules and HA appear to play a role in CRC. Targeting HA-dependent interaction in CRC influences cellular adhesion and may have a potential therapeutic use in treatment of PM in CRC. Further in-vitro and in vivo modelling is needed. Take-home message HA receptor adhesion molecules CD44, RHAMM and ICAM-1 have all been independently implicated in adverse outcomes in colorectal cancer. Targeting HA receptor interaction appears to reduce peritoneal dissemination in colorectal cancer.

New insights in the clinical implication of HOXA5 as prognostic biomarker in patients with colorectal cancer.

Homeobox A5 (HOXA5) is a member of the HOX protein family which is involved in several carcinogenesis pathways, and is dysregulated in many cancer types. However, its expression and function in human colorectal cancer (CRC) is still largely unknown. This study aimed to evaluate HOXA5 expression in Tunisian patients with CRC in order to define new potential biomarker. An immunohistochemical labeling using an HOXA5 antibody was performed on 85 formalin fixed paraffin embedded specimens from patients with CRC. Six normal colon mucosa cases were used as controls. HOXA5 expression showed a cytoplasmic staining in both tumor and stromal/endothelial cells. Loss or low HOXA5 expression was seen in tumor cells in 74/85 cases (87.06%) and in stromal/endothelial cells, in 77/85 (90.59%). In control group of normal colon mucosa HOXA5 was moderately expressed in all the cases. The abnormal expression, was significantly associated to lymph nodes metastasis in tumor cells (p= 0.043) and in stromal/endothelial cells (p= 0.024). HOXA5 immunostaining results suggest the valuable role of this protein in colorectal carcinogenesis. Moreover, the association of lymph node metastasis to HOXA5 abnormal expression underlies its crucial role in colorectal cancer dissemination and prognosis.

Laminin 521 enhances self-renewal via STAT3 activation and promotes tumor progression in colorectal cancer.

Remodeling of basement membrane proteins contributes to tumor progression towards the metastatic stage. One of these proteins, laminin 521 (LN521), sustains embryonic and induced pluripotent stem cell self-renewal, but its putative role in cancer is poorly described. In the present study we found that LN521 promotes colorectal cancer (CRC) cell self-renewal and invasion. siRNA-mediated knockdown of endogenously-produced laminin alpha 5, as well as treatment with neutralizing antibodies against integrin α3β1 and α6β1, were able to reverse the effect of LN521 on self-renewal. Exposure of CRC cells to LN521 enhanced STAT3 phosphorylation, and incubation with STAT3 inhibitors Napabucasin and Stattic was sufficient to block the LN521-driven self-renewal increase. Robust expression of laminin alpha 5 was detected in 7/10 liver metastases tissue sections collected from CRC patients as well as in mouse liver metastasis xenografts, in most cases within areas expressing metastasis cancer stem cell markers such as c-KIT and CD44v6. Finally, retrospective analysis of multiple CRC datasets highlighted the significant association between high LN521 mRNA expression and poor clinical outcome in colorectal cancer patients. Collectively our results indicate that high Laminin 521 expression is a frequent feature of metastatic dissemination in CRC and that it promotes cell invasion and self-renewal, the latter through engagement of integrin isoforms and activation of STAT3 signaling.

Recurrent biliary dissemination of colon cancer liver metastasis: a case report

BackgroundMost colorectal cancer liver metastases form nodules within the hepatic parenchyma, and hepatectomy is the only radical treatment for synchronous metastases. There is concern about intrabiliary tumor growth which may affect the surgical margin, resulting in local recurrence after hepatectomy for colorectal cancer liver metastasis; however, there has been no report of the dissemination in the bile duct after hepatectomy. Here, we report an unusual case of biliary dissemination of colorectal cancer that caused recurrent intrabiliary growth after hepatectomy, and discuss the management of intrabiliary metastasis of colorectal cancer.Case presentationA 69-year-old Japanese man underwent treatment for liver dysfunctions 3 years after aortic valve replacement. Computed tomography revealed an enhanced tumor within the hilar bile duct and dilatation of the left hepatic duct, typical of hilar cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography revealed tumor shadow in his bile duct, and the cytology confirmed malignant cells in the bile. We performed extended left hepatectomy with bile duct resection; his postoperative course remained good without acute complications. After 3 months postoperatively, he was readmitted for subacute cholangitis and obstructive jaundice. Immediately, percutaneous transhepatic cholangiography drainage was performed, followed by cholangiography that exhibited intrabiliary tumor growth in the remnant liver. On immunohistochemical examination, tumor cells were positive for cytokeratin 20 and CDX2 but negative for cytokeratin 7. Then, computed tomography revealed an enhanced tumor-like lesion at the descending colon. After 3 months, left hemicolectomy was performed. Meanwhile, the percutaneous transhepatic cholangiography drainage fluid turned bloody, which was considered to be bleeding from a residual bile duct tumor. Accordingly, radiotherapy was initiated to prevent tumor bleeding around the hilar bile duct, but, unfortunately, the effects were short-lived, and cholangitis rebooted after 1 month leading to our patient’s death due to septic liver failure. Autopsy revealed a remnant tumor in the bile duct, but no noticeable nodular metastasis was observed, except for a single small metastasis in the lower lobe of the left lung.ConclusionsThe intrabiliary growth of metastatic colorectal cancer mimics cholangiocarcinoma occasionally. To date, as the effect of chemotherapy or radiotherapy remains uncertain, the complete resection of a bile duct tumor is the only method which could result in a better prognosis.

Overexpression of Rab11-FIP2 in colorectal cancer cells promotes tumor migration and angiogenesis through increasing secretion of PAI-1

BackgroundRab11 family-interacting protein 2 (Rab11-FIP2) can interact with MYO5B and plays an important role in regulating plasma membrane recycling. However, little is known about the clinical significance of DUSP2 in colorectal cancer (CRC).MethodsIn this study, we investigated Rab11-FIP2 expression by immunohistochemistry in 125 patients with colorectal cancer. Conditioned media containing all secreted factors was harvested. Chemokine secretion and expression were analyzed by Chemi-array.ResultsWe found that the expression level of Rab11-FIP2 was significantly increased in colorectal cancer tissues and high expression of Rab11-FIP2 was closely correlated with nodal metastasis in colorectal cancer patients. Rab11-FIP2 overexpression promoted colorectal cancer metastasis in vitro and in vivo. Finally, we demonstrated that Rab11-FIP2 overexpression may contribute to increased secretion of PAI-1 in human colorectal cancer cells.ConclusionsOur findings reveal a novel mechanism underlying the role of Rab11-FIP2 in colorectal cancer dissemination, suggesting that targeting Rab11-FIP2 might be a promising therapeutic strategy for CRC.

The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer.

In colorectal cancer (CRC), RHAMM is an independent adverse prognostic factor. The aim of the study was therefore to investigate on the role of RHAMM as a potential direct driver of cell proliferation and migration in CRC cell lines and to identify pathways dependent on RHAMM in human CRC.Proliferation, cell cycle alterations and invasive capacity were tested in two RHAMM- and control- knockdown CRC cell lines by flow cytometry and in vitro assays. Tumorigenicity and metastasis formation was assessed in immunodeficient mice. RNA-Seq and immunohistochemistry was performed on six RHAMM+/- primary CRC tumors.In vitro, silencing of RHAMM inhibited CRC cell migration and invasion by 50% (p<0.01). In vivo, RHAMM knockdown resulted in slower growth, lower tumor size (p<0.001) and inhibition of metastasis (p<0.001). Patients with RHAMM-high CRC had a worse prognosis (p=0.040) and upregulated pathways for cell cycle progression and adhesion turnover.RHAMM overexpression is correlated with increased migration and invasion of CRC cells, leads to larger, fast growing tumors, and its downregulation essentially abolishes metastasis in mouse models. RHAMM is therefore a promising therapeutic target in all CRC stages as its inhibition affects growth and dissemination of the primary CRC as well as the metastases.

Colorectal Cancer Metastases Settle in the Hepatic Microenvironment Through α5β1 Integrin.

Colorectal cancer (CRC) metastasis dissemination to secondary sites represents the critical point for the patient's survival. The microenvironment is crucial to cancer progression, influencing tumour cell behaviour by modulating the expression and activation of molecules such as integrins, the cell-extracellular matrix interacting proteins participating in different steps of the tumour metastatic process. In this work, we investigated the role of α5β1 integrin and how the microenvironment influences this adhesion molecule, in a model of colon cancer progression to the liver. The culture medium conditioned by the IHH hepatic cell line, and the extracellular matrix (ECM) proteins, modulate the activation of α5β1 integrin in the colon cancer cell line HCT-116, and drives FAK phosphorylation during the process of cell adhesion to fibronectin, one of the main components of liver ECM. In these conditions, α5β1 modulates the expression/activity of another integrin, α2β1, involved in the cell adhesion to collagen I. These results suggest that α5β1 integrin holds a leading role in HCT-116 colorectal cancer cells adhesion to the ECM through the modulation of the intracellular focal adhesion kinase FAK and the α2β1 integrin activity. The driving role of the tumour microenvironment on CRC dissemination, here detected, and described, strengthens and adds new value to the concept that α5β1 integrin can be an appropriate and relevant therapeutic target for the control of CRC metastases.

Abstract 3248: Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer.

Abstract Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contacts. Interestingly, the treatment of mice before and after inoculation significantly suppressed the cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK, including TAE226, appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms. Citation Format: Munenori Takaoka, Hui-fang Hao, Xiao-hong Bao, Yasuko Tomono, Kazufumi Sakurama, Toshiaki Ohara, Takuya Fukazawa, Tomoki Yamatsuji, Yoshio Naomoto. Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3248. doi:10.1158/1538-7445.AM2013-3248

Relationship between the Expression of the Extracellular Matrix Genes SPARC, SPP1, FN1, ITGA5 and ITGAV and Clinicopathological Parameters of Tumor Progression and Colorectal Cancer Dissemination

Objective: To evaluate the relationship between the expression of the extracellular matrix (ECM) genes SPARC, SPP1, FN1, ITGA5 and ITGAV and the histopathologic parameters of neoplastic progression and colorectal carcinoma (CRC) dissemination. Methods: A retrospective study was conducted in 114 patients with stage I–IV CRC who underwent primary tumor resection. Quantitative real-time PCR and immunohistochemistry (IHC) assays were performed in samples obtained from the primary tumors. The correlation between the expression of these markers and the expression of p53, Bcl-2, Ki67, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor was assessed with the Spearman coefficient (r). Results: The ITGAV gene was found to be significantly amplified in tumors with positive perineural invasion (p = 0.028). Expression of the SPARC, SPP1, FN1, ITGA5 and ITGAV genes did not correlate with TNM staging. A direct relationship between ITGAV and EGFR expression (r = 0.774; p < 0.001) was observed by IHC. Conclusions: ECM gene expression did not correlate with classical prognostic factors for CRC, but overexpression of the ITGAV gene and protein was correlated with an increased risk of perineural invasion. The relationship between ITGAV and EGFR expression suggests the possibility of crosstalk in this signal pathway.

Abstract 2165: Genomic profiling of colorectal cancers from patients diagnosed with circulating tumor cells

Abstract Introduction. Colorectal cancer (CRC) is the second leading cause of cancer related deaths, due to the development of distant metastases in many CRC patients. To detect metastatic disease in early stage, the identification of tumor cells circulating in the peripheral blood of patients (CTCs) is of outmost importance. Several techniques have recently been developed which can detect CTCs, two of them are the CellSearch® system and the EpiSpot assay. We have investigated genomic aberrations and gene expression patterns in primary colorectal tumors in correlation with CTC status of patients. This may lead to the identification of the underlying mechanisms of metastatic spread and potential new markers for detecting the tumor's capability to disseminate. Methods. Peripheral blood of 48 colorectal patients was investigated by CellSearch® and EpiSpot for CTCs. Samples with at least one CTC, detected with either the CellSearch® system or the EpiSpot assay were considered as positive. Genomic DNA and mRNA extracted from the primary tumors of the same patients were investigated with Illumina based Comparative Genomic Hybridization (CGH) and Gene Expression profiling (GEP) microarrays. CGH arrays covered the whole genome with an average resolution of 5kb and GEP arrays covered more than 25,000 annotated genes. Results. Twenty-nine patients were diagnosed to be positive for CTCs, either with the EpiSpot assay or the CellSearch® system; negative for CTCs in both assays were 17 blood samples. Array-CGH showed that primary tumors from CTC positive patients harbored significantly more often loss of chromosome 15q11 (Fisher's exact test, p&amp;lt;0.01). The Significance Analysis of Microarrays (SAM) revealed 13 genes to be differentially expressed between both groups. These genes are mainly involved in kinase activity and ATP-binding, and are located in the plasma membrane. Furthermore, CYFIP1 was downregulated in colorectal tumors from CTC positive patients compared with CTC negative patients which correlated with its loss detected with array-CGH. CYFIP1 is a known putative invasion suppressor gene in epithelial cancers. Conclusion. Our results suggest that several molecular and genomic profiles can be identified as marker for tumor cell dissemination in CRC. More over, significant correlation between CTC status and the primary tumor's genomic profile indicates a biological rationale for tumor cell dissemination rather than a random effect or shedding of cells. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 2165.

Comprehensive Management of Disseminated Colorectal Cancer

In 1977, Foster and Berman published a book showing surprising long-term benefits from the resection of liver tumors. 1 Adson and colleagues from the Mayo Clinic in 1984 focused on the resection of isolated dissemination of colorectal cancer to the liver. 2 Shortly thereafter, Hughes and colleagues reinforced these data by publishing a multiinstitutional registry of colorectal cancer metastases. This survey of 859 patients established a survival rate of approximately 30% in this large group of patients previously expected to have a 0% 5-year survival. 3 Hughes and colleagues also established the pattern of failure to be expected after liver resection. 4 Fernandez-Trigo and colleagues constructed a similar registry of repeat liver resections for colorectal cancer. 5 They established that reoperation in this clinical setting was equally beneficial to the first resection. Numerous publications have established the prognostic indicators to be used to select these patients. 6,7 However, no single clinical feature, such as multiple liver metastases, could be used as an absolute contraindication to liver resection. Even patients with concomitant liver metastases and other sites of disseminated disease could benefit from cancer resection. 8,9 The single clinical requirement necessary for a potentially curative surgical intervention was complete resection of all sites of disease. As the requirement for complete resection of colorectal liver metastases was recognized as an absolute requirement of long-term benefit, Adam and colleagues developed treatment strategies to convert unresectable to resectable disease. 10 Neoadjuvant chemotherapy with 5-fluorouracil

Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination

Invasion and metastasis are the deadly face of malignant tumors. Considering the high rate of incidence and mortality of colorectal cancer, it is critical to determine the mechanisms of its dissemination. In the parallel investigation of the invasive front and tumor center area of colorectal cancer (CRC), observation of heterogeneous beta-catenin distribution and epithelial-mesenchymal transition (EMT) at the invasive front suggested that there might be a crosstalk between tumor cells and the tumor microenvironment. Wnt signaling pathway is also involved in the cancer progression due to its key role in CRC tumorigenesis. Moreover, in recent years, there is increasing evidence that the regulators of microenvironment, including extracellular matrix, growth factors and inflammatory factors, are associated with the activation of Wnt pathway and the mobility of tumor cells. In this review, we will try to explain how these molecules trigger metastasis via the Wnt pathway.

Functional imaging of colorectal cancer angiogenesis

Angiogenesis is a key factor in the growth and dissemination of colorectal cancer, with significant implications for its clinical management. Previous trials have provided proof-of-principle that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment for this disease. Characterisation of the angiogenic status of the tumour on an individual patient basis could allow for a more targeted approach to treatment. In vivo imaging techniques that assess tumour microvessel function have the potential to improve the management of treatment for patients with colorectal cancer. This review focuses on MRI and CT assessment of colorectal cancer angiogenesis. We discuss the effects that these two techniques have had in the assessment of this disease, including tumour staging and therapeutic assessment. Their comparability with other imaging techniques, in particular ultrasound, and their limitations are also addressed.

MMP-1 (collagenase-1) expression in primary colorectal cancer and its metastases

Objective. The role of MMP-1 (collagenase-1) in the development of a metastatic phenotype in colorectal cancer (CRC) has not been fully studied. The aim of this study was to investigate the mechanisms involved in the dissemination of CRC by examining the expression of MMP-1 in the primary tumours and their metastases, with special reference to standard clinicopathological features and disease outcome. Material and methods. Surgical specimens from the primary tumours (P) and their metastatic (M) lesions were available from 30 patients with Stage II, III and IV CRC, and were subjected to immunohistochemical (IHC) staining for MMP-1. Both cytoplasmic expression in cancer cells (CC) and stromal (ST) expression were related to pertinent clinical and follow-up data. Results. In a pairwise comparison of P-M pairs, CC expression (but not ST expression) in P and M was significantly different (Wilcoxon rank test, p=0.037). Strong CC expression in P was significantly related to the presence of lymph node involvement at diagnosis (p=0.008). CC expression in M was intense only in metachronous metastases (Stage II/III disease) but never in synchronous metastases (Stage IV) (p=0.034). There was a significant down-regulation of CC (p=0.004) in liver metastasis (n=9) in comparison with all other metastatic sites (n=21). ST expression in P (but not in M) showed a linear decrease in parallel with increasing stage (p=0.028 for linear trend). MMP-1 expression was not significantly associated with any other clinicopathological variables, including age, gender, carcinoembryonic antigen (CEA) or patients’ disease-free or overall survival. Conclusions. These data suggest that MMP-1 may play an important role in tumour invasion and metastasis of CRC.

Intra-abdominal patterns of disease dissemination in colorectal cancer identified using radioimmunoguided surgery

Patterns of metastatic spread are difficult to determine with routine postoperative follow-up. This study was undertaken to evaluate two selected populations of colorectal cancer patients injected and screened with anti-tumor antibody. Eighty-six evaluable patients with colorectal cancer underwent exploratory laparotomy with both traditional surgical exploration and radioimmunoguided surgery (RIGS) following injection of 125I-labeled CC49 monoclonal antibody. RIGS-positive tissue detectable with a handheld gamma-detecting probe was defined as tissue involved with the disease process. Comparisons were made between extent of disease using traditional exploration and extent using RIGS. In 41 patients with primary disease, traditional exploration detected 45 sites of disease (1.1 sites/patient) compared with 153 RIGS-positive sites (3.7 sites/patient). In 45 patients with recurrent disease, traditional exploration found 116 sites (2.6 sites/patient) vs. 184 RIGS-positive sites (4.1 sites/patient). Involvement by selected anatomic sites is shown below [Table: see text]. RIGS detected more tissue involved in disease process for all sites in both primary and recurrent disease except liver metastases. Areas with highest proportion of RIGS-positive tissue, the gastrohepatic ligament and celiac nodes, are rarely resected and are not pathologically examined. Positive RIGS localization of tumor antigen in these areas suggests more extensive dissemination of disease process.

High frequency of allelic deletion on chromosome 17p in advanced colorectal cancer.

Colorectal cancers often show allelic loss of chromosomes 5q and 17p, regions where the tumor suppressor genes p53 and adenomatous polyposis coli are known to reside. Currently, the inactivation of tumor suppressor genes and the activation of oncogenes are considered major events involved in tumor development. According to a recent genetic model, ras gene mutations and allelic deletion of chromosome 5q are early changes, whereas chromosome 17p and 18q deletions are late changes in colorectal tumorigenesis. It has been shown that 17p and 18q deletions are associated with an increased tendency of disease dissemination in colorectal cancer. Most of the studies on allelic deletion in colorectal cancer were undertaken with Western population cohorts. The authors examined the association of chromosomes 5q and 17p deletions with clinical parameters, including metastasis in a predominantly Chinese population with a high incidence of colorectal cancer. Allelic deletion was studied with the restriction fragment length polymorphism technique in tumors from 102 and 100 sporadic colorectal cancer cases for chromosomes 5q and 17p, respectively. Probes pi 227 and ECB27 were used for chromosome 5q, and probe YNZ22.1 was used for chromosome 17p. 5q Deletion was found in 33% of informative cases, whereas 17p deletion was seen in 69% of informative cases. 17p Allelic loss showed significant association with Dukes' Stage D as well as the presence of distant metastasis, whereas 5q deletion showed no such association. Allelic loss on chromosome 17p may be a useful prognostic marker in cases of colorectal cancer.