Histochemical localization of caldesmon isoforms in colon adenocarcinoma and lymph node metastases

Köhler, Christoph

doi:10.1007/s00428-011-1091-0

Cited by 8 publications

(7 citation statements)

References 49 publications

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“…L‐caldesmon is one of the isoforms generated by the selective splicing, which is widely expressed and localized in podosomes . Interestingly, L‐caldesmon expression was reported to be found in cancer‐associated fibroblasts and blood vessels of the tumor stroma . L‐caldesmon expression in the tumor stroma also may contribute to tumor progression through biological or mechanical manners.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer

Yokota

Kojima

Higuchi

et al. 2015

Intl Journal of Cancer

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Tumors can create a heterogenetic tumor microenvironment. We recently identified the pathologically unique cancer microenvironment formed by peritoneal invasion (CMPI), and revealed that subperitoneal fibroblasts (SPFs) within peritoneal tissue play a crucial role in tumor progression through their interaction with cancer cells. Therefore, the genes in SPFs altered by cancer stimulation may include some biologically important factors associated with patient prognosis. In this study, we aimed to identify new biomarkers using genes specifically upregulated in SPFs by cancer-cell-conditioned medium (CCCM) stimulation (SPFs CCCM response genes; SCR genes) in colon cancer (CC). We constructed two frameworks using SCR gene data: a publicly released microarray dataset, and validation cases with freshly frozen CC samples to identify genes related to short recurrence-free survival (RFS). In the first framework, we selected differentially expressed genes between the high and low SCR gene expression groups. In the second framework, genes significantly related to short RFS were selected by univariate analysis using all SCR genes, and multivariate analysis was performed to select robust genes associated with short RFS. We identified CTGF, CALD1, INHBA and TAGLN in the first framework, and PDLIM5, MAGI1, SPTBN1 and TAGLN in the second framework. Among these seven genes, high expression of three genes (CALD1, TAGLN and SPTBN1) showed a poor prognosis in our validation cases. In a public microarray dataset, SCR gene expression was associated with the expression of ECM component, EMT, and M2-macrophage associated genes, which was concordant with the pathological features of CMPI. Thus, we successfully identified new prognostic factors.In the cancer microenvironment (CME), cancer cells are surrounded by fibroblasts, vessel component cells, inflammatory cells including lymphocytes and macrophages, and the extracellular matrix (ECM) produced by these stromal cells. Fibroblasts were first described in the late 19th century as the nonvascular, nonepithelial and noninflammatory cells of connective tissue, and are the most common of all stromal cells that compose the CME.1 Fibroblasts are also a major source of the ECM component that provides a scaffold for the growth and differentiation of normal epithelial cells, and they are activated in the process of wound healing. 2 However, activated fibroblasts are known to accelerate tumor growth and metastasis. Some growth factors and ECM-remodeling proteases such as matrix metalloproteinases (MMPs) are produced by activated fibroblasts, which contribute to tumor growth and metastasis. [3][4][5] In addition, activated fibroblasts express a-smooth muscle actin (a-SMA) and generate great contractile force. 6 This high contractile activity leads to increased ECM stiffness, which is known to increase the migration activity of cancer cells. 7-10 Thus fibroblasts affect the characteristics of the CME and even cancer progression itself through both a biological and mechanical manner. The gastrointes...

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Section: Discussionmentioning

confidence: 99%

Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer

Yokota

Kojima

Higuchi

et al. 2015

Intl Journal of Cancer

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“…Specifically, it has been shown, by immunohistochemistry with three different antibodies against human caldesmon isoforms, that the longest h‐caldesmon isoform is mainly expressed in smooth muscle cells and also in pericryptal fibroblasts in the colon. In colorectal adenocarcinomas, h‐caldesmon expression is markedly reduced in large areas of the stroma and cancer epithelium did not stain for h‐caldesmon; lymph‐node metastases also displayed little h‐caldesmon immunoreactivity of the stroma (Kohler, 2011). Our results match those of this study, as this long isoforms down‐regulated at both mRNA and protein level (Figures 4 and 5).…”

Section: Discussionmentioning

confidence: 99%

“…AS events of caldesmon have already been reported between CRC and normal colon tissue, probably reflecting the involvement of AT with specific roles in these important processes (Gardina et al., 2006; Thorsen et al., 2008). It has also been demonstrated that caldesmon isoforms, encoded by the CALD‐1 gene, are differentially expressed in tumor tissue and stroma embedded in colon adenocarcinoma and metastatic tissue (Kohler, 2011). Specifically, it has been shown, by immunohistochemistry with three different antibodies against human caldesmon isoforms, that the longest h‐caldesmon isoform is mainly expressed in smooth muscle cells and also in pericryptal fibroblasts in the colon.…”

Section: Discussionmentioning

confidence: 99%

An integrative framework identifies alternative splicing events in colorectal cancer development

et al. 2013

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Alternative splicing (AS) is a common mechanism which creates diverse RNA isoforms from a single gene, potentially increasing protein variety. Growing evidence suggests that this mechanism is closely related to cancer progression. In this study, whole transcriptome analysis was performed with GeneChip Human exon 1.0 ST Array from 80 samples comprising 23 normal colon mucosa, 30 primary colorectal cancer and 27 liver metastatic specimens from 46 patients, to identify AS events in colorectal cancer progression. Differentially expressed genes and exons were estimated and AS events were reconstructed by combining exon-level analyses with AltAnalyze algorithms and transcript-level estimations (MMBGX probabilistic method). The number of AS genes in the transition from normal colon mucosa to primary tumor was the most abundant, but fell considerably in the next transition to liver metastasis. 206 genes with probable AS events in colon cancer development and progression were identified, that are involved in processes and pathways relevant to tumor biology, as cell-cell and cell-matrix interactions. Several AS events in VCL, CALD1, B3GNT6 and CTHRC1 genes, differentially expressed during tumor development were validated, at RNA and at protein level. Taken together, these results demonstrate that cancer-specific AS is common in early phases of colorectal cancer natural history.

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“…There are two alternatively spliced isoforms of CaD, high (h-CaD) and low (l-CaD), which differ in their molecular weight. H-CaD levels are lower in the late stages of colorectal adenocarcinoma while the low-molecular weight variant expression varies during tumor development and it is related to metastasis (Köhler, 2011;Kim et al, 2012). CaD is absent in the stroma in CRC but present in smooth muscle, thus it is a marker for desmoplasia and tumor invasiveness of the large intestine's muscularis propria (Roberts et al, 2014).…”

Section: Cox-2 and The Tgf-b Pathwaymentioning

confidence: 99%

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

et al. 2020

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Colorectal cancer (CRC) is one of the most common and recurrent types of cancer, with high mortality rates. Several clinical trials and meta-analyses have determined that the use of pharmacological inhibitors of cyclooxygenase 2 (COX-2), the enzyme that catalyses the rate-limiting step in the synthesis of prostaglandins (PG) from arachidonic acid, can reduce the incidence of CRC as well as the risk of recurrence of this disease, when used together with commonly used chemotherapeutic agents. These observations suggest that inhibition of COX-2 may be useful in the treatment of CRC, although the current drugs targeting COX-2 are not widely used since they increase the risk of health complications. To overcome this difficulty, a possibility is to identify genes regulated by COX-2 activity that could give an advantage to the cells to form tumors and/or metastasize. The modulation of those genes as effectors of COX-2 may cancel the beneficial effects of COX-2 in tumor transformation and metastasis. A review of the available databases and literature and our own data have identified some interesting molecules induced by prostaglandins or COX-2 that have been also described to play a role in colon cancer, being thus potential pharmacological targets in colon cancer. Among those mPGES-1, DUSP4, and 10, Programmed cell death 4, Trop2, and many from the TGFb and p53 pathways have been identified as genes upregulated in response to COX-2 overexpression or PGs in colon carcinoma lines and overexpressed in colon tumor tissue. Here, we review the available evidence of the potential roles of those molecules in colon cancer in the context of PG/ COX signaling pathways that could be critical mediators of some of the tumor growth and metastasis advantage induced by COX-2. At the end, this may allow defining new therapeutic targets/drugs against CRC that could act specifically against tumor cells and would be effective in the prevention and treatment of CRC, lacking the unwanted side effects of COX-2 pharmacological inhibitors, providing alternative approaches in colon cancer.

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Histochemical localization of caldesmon isoforms in colon adenocarcinoma and lymph node metastases

Cited by 8 publications

References 49 publications

Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer

Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer

An integrative framework identifies alternative splicing events in colorectal cancer development

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

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