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Background: Four-and-a-half LIM domains protein 2 (FHL2) is a component of the focal adhesion structures and has been suggested to have a role in cancer progression. It has been shown to be overexpressed in the colorectal cancer (CRC).Methods: Here, we examined a possible prognostic value of FHL2 in CRC. Immunohistochemistry for FHL2 was performed on 296 CRCs without distant metastases at the time of surgery. Staining in the epithelial compartment was quantitatively evaluated using image analysis, and results were related to clinical variables. Antibody specificity was tested using small-interfering RNA transfection in hTERT-immortalised myofibroblasts.Results: Varying degrees of cytoplasmic FHL2 expression by neoplastic epithelial cells were detectable in all cases. Higher FHL2 expression in the epithelial compartment was an independent adverse prognostic factor. Multivariate Cox analysis shows that expression in the tumour invasion front (P<0.001) as well as in the centre of the tumour (P<0.001) was associated with metachronous metastases independently of the clinicopathological variables; expression in the tumour invasion front was also associated with overall survival independently of the clinicopathological variables (P<0.01).Conclusion: Higher FHL2 expression is involved in CRC progression and correlates with the development of metachronous metastases and overall survival, suggesting that FHL2 is an independent adverse prognostic indicator for CRC. [ABSTRACT FROM AUTHOR]

Desmoid tumours are locally invasive soft tissue tumours in which ß-catenin mediated TCF-dependent transcription is activated. The role of soluble factors secreted by the myofibroblastic desmoid tumour, which could stimulate tumour invasiveness, was investigated. Using collagen gel invasion assays, the presence of factors stimulating invasion in desmoid conditioned media (CM) could be established. Since matrix metalloproteinases (MMPs) have been implicated in the process of tumoral invasion, the expression levels of the MMP family members were evaluated. Quantitative reverse transcription-PCR was used to determine the expression levels of MMP1, MMP2, MMP3, MMP7, MMP11, MMP12, MMP13, MMP14 and the inhibitors TIMP1, TIMP2 and TIMP3. Besides overexpression of MMP7, a known TCF-dependent target gene, a striking upregulation of the expression levels of MMP1, MMP3, MMP11, MMP12 and MMP13 in desmoid tumours, compared to unaffected fibroblasts from the same patients, was found. Treating the CM of desmoids with a synthetic and a physiologic MMP inhibitor reduced the invasion-stimulating capacity of the desmoid CM by approximately 50%. These results suggest the involvement of soluble factors, released by the desmoid cells, in stimulating invasion and implicate the MMPs as facilitators of invasion.British Journal of Cancer (2004) 90, 1443-1449. doi:10.1038/sj.bjc.6601661 www.bjcancer.com Published online 23 March 2004 [ABSTRACT FROM AUTHOR]

Malignant cancer cells do not act as lone wolves to achieve metastasis, as they exist within a complex ecosystem consisting of an extracellular matrix scaffold populated by carcinoma-associated fibroblasts (CAFs), endothelial cells and immune cells (De Wever and Mareel, J Pathol, 2003; De Wever et al., Int J Cancer, 2008; De Wever et al., Semin Cancer Biol., 2014). Paracrine interactions between CAFs, also termed myofibroblasts, and cancer cells stimulate invasion of colon cancer cells in matrix scaffolds. The pro-invasive activity was found also with the secretome and we identified the combined action of Scatter Factor/Hepatocyte Growth Factor (SF/HGF) and tenascin-C (TNC) to promote invasion (De Wever et al., FASEBJ, 2004). Secretome proteomics revealed the presence of multiple other pro-metastatic proteins suggesting that the molecular characteristics of a CAF remain in evolution (De Boeck et al., Proteomics, 2013). CAFs show operational flexibility; eg their ability to respond dynamically to a cancer cell’s fluctuating demands by shifting profitable signals necessary in metastasis. Local, tissue-resident fibroblasts and mesenchymal stem cells (MSCs) coming from reservoir sites such as bone marrow (BM) are the main progenitor cells of CAFs (De Boeck et al., Oral Oncol, 2010). A successful invader must survive in an ectopic environment and CAFs provide advantageous signals to cancer cells to accomplish survival through AKT activation. Neuregulin (NRG)-1 secreted by CAFs increase cancer cell number through HER2/HER3-dependent activation of the PI3K/AKT pathway. Translational data demonstrate transmembrane NRG-1 expression in CAF in primary colorectal cancer and in liver metastasis, with the strongest expression in the immediate vicinity of HER2/HER3 expressing cancer cells. Moreover, high transmembrane NRG-1 expression is a poor prognosis marker in colorectal cancer (De Boeck et al., GUT, 2013). The odds that an aggressive cancer cell will form a metastatic colony in some organ are vanishingly small. Nevertheless, metastasis is responsible for more than 90% of cancer-associated mortality; thus the clinical need to prevent or target metastasis is high. Viewing cancer within the context of ecosystems may provide opportunities to exploit CAFs to create tumor-environment bio-mimetics to deceive and redirect metastatic cancer cells. [ABSTRACT FROM AUTHOR]

Rab GTPases, which are Ras-like small GTPases, are involved in microtubule and actin dependent intracellular vesicle movement and are key players in regulation of endo-and exocytosis. Rab27a and rab27b, members of the rab27 subfamily, show 72% amino acid sequence homology and are functionally redundant in platelets and endocrine cells. We found that rab27b is highly expressed in several human melanoma cell lines but very lowly in human primary melanocytes. Differential expression of rab27b in melanoma cell lines and its potential role in tumour progression remains poorly understood. Here we show that over-expression of enhanced green fluorescent protein (eGFP) tagged rab27b induced aggressive invasion of the human non invasive VKR melanoma cell line, invasive VQL melanoma cell line and primary melanocytes into collagen type I whereas eGFP tagged rab27a and eGFP did not. Invasion of eGFP-rab27b melanocytes was accompanied by stress fibber formation and alteration of the dendritic phenotype. Pull down assays demonstrated that active Rho was up regulated in eGFP-rab27b melanocytes. Co-expression of Rac1N17 RhoAN19 with eGFP rab27b counteracted rab27b-induced invasion, suggesting a requirement for Rac and Rho activity in the invasion process. Rab27b dependent invasion was also antagonized by introduction of a dominant negative myosin Va construct, which is known to interact with rab27b positive vesicles. We conclude that rab27b specific expression stimulates invasion and migration of melanoma cell lines and primary melanocytes into collagen type I by Rac/Rho signaling. [ABSTRACT FROM AUTHOR]

Inflammation has a significant impact on cervical cancer (CC) development and therapy response. We sought to determine if splenic metabolic activity reflects host immune status and could improve prognostic and predictive categorization of CC. Ninety-two consecutive patients with FIGO stage IB1 to IVB CC who received neo-adjuvant (chemo)radiation (NA-CRT) with curative intent were included. PET scans were performed at diagnosis and after completion of the NA-CRT. PET images were retrospectively assessed for pretreatment spleen-to-liver SUV ratio (preSLR), posttreatment spleen-to-liver SUV ratio (postSLR) and ΔSLR (post-pre) on Oasis Nuclear Medicine Workstations. (Δ)SLR was calculated as both (Δ)SLR max and (Δ)SLR mean. The prognostic (DFS) and predictive (pCR) abilities of these variables together with established predictors were calculated by C-index and ROC analysis, respectively. The optimal long-rank statistic and Youden index determined cutoff values. Multivariate Cox proportional hazard regression models were ranked based on their Akaike information criterion (AIC). Clinicopathological differences between patients with low or high SLR were performed by chi-square and Mann-Whitney U tests. For preSLR max and preSLR mean , association with DFS was found for preSLR max >0.92 with HR = 2.25 (95% CI (1.08-4.66); p = 0.026) and for preSLR mean >0.94 with HR = 2.79 (95% CI (1.33-5.86); p = 0.005), respectively. The selected multivariate model consisted of three factors: preSLR max , ΔSLR max and parametrial invasion (dichotomized; HR = 6.40 95% CI (2.70-15.20); p < 0.001). The model's prognostic ability was quite favorable compared to FIGO staging (C-index 0.69 vs. 0.64). Further, uni- and multivariate analyses suggest that both low preSLR max and low preSLR mean influence pCR. Patients (n = 31) with high preSLR max had a higher density of CD3+,CD4+, CD8+, CD20+(77.8% vs. 36.4%; p = 0.036), CD68+ (88.9% vs. 40.9%; p = 0.015), CD163+, FoxP3+and PD-L1+immune cells, as well as PD-L1+tumor cells (85.7% vs. 55.6%; p = 0.019) in the primary tumor using IHC; the same trends were observed for preSLR mean SLR is a promising prognostic and predictive biomarker in CC and is associated with the tumor immune infiltrate. Ghent University Hospital. Research Foundation-Flanders (FWO). E.A. De Jaeghere: Travel / Accommodation / Expenses: PharmaMar. F. Laloo: Honoraria (institution): Bayer. K. De Man: Travel / Accommodation / Expenses: Bayer. H. Denys: Honoraria (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (institution), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Teva; Honoraria (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (institution): Eli Lilly and Company; Honoraria (institution): Novartis; Honoraria (institution): Amgen; Honoraria (institution): Tesaro. K. Vandecasteele: Travel / Accommodation / Expenses: PharmaMar. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]