Hepatic Stellate Cells Promote Liver Metastasis of Colon Cancer Cells by the Action of SDF-1/CXCR4 Axis

Matsusue, Ryo; Kubo, Hajime; Hisamori, Shigeo; Okoshi, Kae; Takagi, Hidekazu; Hida, Koya; Nakano, Keiko; Itami, Atsushi; Kawada, Kenji; Nagayama, Satoshi; Sakai, Yoshiharu

doi:10.1245/s10434-009-0599-x

Cited by 132 publications

(114 citation statements)

References 26 publications

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“…To investigate the number of CXCR3-or CXCR4-positive cells, we first chose three arbitrary sites under the microscope (original magnification, 400Â) and counted the cancer cells, as described previously. 12 We then calculated the proportion of CXCR3-or CXCR4-positive cells within the counted region.…”

Section: Immunohistochemistrymentioning

confidence: 99%

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Murakami

Kawada

Iwamoto

et al. 2012

Intl Journal of Cancer

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115

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Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis. We previously demonstrated that forced expression of CXCR3 promotes colon cancer metastasis preferentially to the draining lymph nodes (LNs), with poor prognosis. Using clinical colorectal cancer (CRC) samples, here, we show that expressions of CXCR3 and CXCR4 are significantly higher in metastatic foci within LNs and liver compared to primary tumors, whereas ligands for CXCR3 and CXCR4 are not. We also have demonstrated that some human CRC cell lines constitutively express both CXCR3 and CXCR4, and that activation of CXCR3 strengthens the CXCR4‐mediated cell migration in vitro in a synergistic manner. By constructing SW620 cell lines with reduced expression of CXCR3 and/or CXCR4 using microRNA, we investigated in vivo metastatic activities in a mouse rectal transplantation model. Six weeks after inoculation, CXCR3‐, CXCR4‐, and CXCR3/CXCR4 double‐knockdowns significantly reduced metastasis to LNs, liver and lungs, compared to the control (p < 0.05). Importantly, its suppressive effect on LN metastasis was significantly stronger in CXCR3‐ and CXCR3/CXCR4 double‐knockdowns. In addition, CXCR3‐ and CXCR3/CXCR4 double‐knockdowns significantly decreased the dissemination of cancer cells to liver and lungs, even after 2 weeks. These results indicate that targeting CXCR3 and CXCR4 can be a promising therapy against CRC metastasis.

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Section: Immunohistochemistrymentioning

confidence: 99%

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Murakami

Kawada

Iwamoto

et al. 2012

Intl Journal of Cancer

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115

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“…SDF-1 is expressed by stromal cells, such as fibroblasts and endothelial cells (16). In colorectal cancer, elevated SDF-1 expression is associated with metastasis and poor prognosis (17,18).…”

Section: Introductionmentioning

confidence: 99%

Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy

Saigusa

Toiyama²,

Yokoe³

et al. 2011

Int J Oncol

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Abstract. Cancer-associated fibroblasts (CAFs) in the stroma play an important role in influencing the proliferation, invasion and metastasis of cancer cells. Fibroblast activation protein-α (FAP-α) is known as a marker of CAFs, while stromal cell-derived factor-1 (SDF-1) is primarily expressed by CAFs. Herein, we investigated whether the expression levels of these genes are associated with clinical outcome after pre-operative chemoradiotherapy (CRT) in rectal cancer patients. We obtained total RNA from residual cancer stroma using microdissection from a total of 52 rectal cancer specimens from patients who underwent pre-operative CRT, we performed transcriptional analyses, and the serum protein concentrations in 40 matched microdissected specimens were measured by enzyme-linked immunosorbent assay. Additionally, we sought to clarify the location of FAP-α and SDF-1 expression using immunohistochemical staining. Of the 52 patients, 15.6 and 36.8% showed detectable FAP-α and SDF-1 mRNA expression, respectively. A significant correlation was observed between stromal FAP-α and SDF-1 mRNA levels. Moreover, there was a significant correlation between stromal SDF-1 gene expression levels and serum protein levels. Patients who developed distant recurrences after CRT had positive expression of both genes (P<0.05). The positive expression of both genes was also associated with poor probability of recurrence-free and overall survival (P<0.05). Patients with elevated serum SDF-1 levels had equally poor overall survival as those with positive stromal SDF-1 gene expression (P<0.05). In immunohistochemistry, both FAP-α and SDF-1 expression was observed in certain activated fibroblasts. In conclusion, FAP-α and SDF-1 expression was shown to be involved in tumor re-growth and recurrence in rectal cancer patients treated with pre-operative CRT.

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“…CXCL12 is a chemokine expressed by both cancer and stromal cells (21,22). Reportedly, CXCL12 and its receptor, CXCR4, play important roles in local progression, dissemination and immune evasion of colorectal cancer cells (23)(24)(25). Our recent study also suggested that stromal CXCL12 and CXCR4 expression following preoperative CRT is associated with distant recurrence and poor prognosis in RC (15).…”

Section: Univariate Analysismentioning

confidence: 83%

Clinical significance of enlarged lateral pelvic lymph nodes before and after preoperative chemoradiotherapy for rectal cancer

Inoue

Saigusa

Hiro

et al. 2016

Molecular and Clinical Oncology

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Abstract. Preoperative chemoradiotherapy (CRT) with total mesorectal excision (TME) is the widely accepted treatment for rectal cancer (RC) in Western countries. However, there remains controversy as to whether preoperative CRT is useful in tumors that extend beyond the mesorectum, including metastasis to the lateral pelvic lymph nodes (LPLN). The aim of this study was to assess the prognostic significance of LPLN enlargement in patients with RC who receive preoperative CRT followed by TME without LPLN dissection. We evaluated the prognostic effect of radiographic LPLN enlargement before and after CRT, as well as the patients' clinicopathological and genetic profiles. Of the 104 patients investigated, pretreatment imaging identified 19 (18%) as LPLN-positive (>7 mm in diameter). Of these 19 patients, 7 (37%) exhibited LPLN downsizing to <7 mm following CRT. The median follow-up period was 52 months. The 5-year cancer-specific survival (CSS) or relapse-free survival (RFS) did not differ significantly between patients who did and those who did not have positive LPLN on pretreatment imaging. However, LPLN that remained positive after CRT were significantly associated with poorer 5-year CSS (73 vs. 84%, respectively; P=0.0052) and RFS (32 vs. 78%, respectively; P=0.0264). None of the patients whose LPLN were downsized to <7 mm following CRT developed recurrence; however, those with positive LPLN after CRT had a 55% higher recurrence rate, characterized by delayed local recurrence, a pattern that may be affected by certain chemokines. In conclusion, changes in initially positive LPLN (>7 mm) may predict the prognosis of patients with RC who receive preoperative CRT-TME. LPLN positivity after CRT was associated with shorter CSS and RFS. Strategies to improve patient survival may include selective LPLN dissection or more aggressive multimodality therapy.

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Hepatic Stellate Cells Promote Liver Metastasis of Colon Cancer Cells by the Action of SDF-1/CXCR4 Axis

Abstract: These results suggest that HSCs play important role in liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis and provide preclinical evidence that blockade of the axis is a target for antimetastasis therapy.

Cited by 132 publications

References 26 publications

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy

Clinical significance of enlarged lateral pelvic lymph nodes before and after preoperative chemoradiotherapy for rectal cancer

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