Ras-induced Modulation of CXCL10 and Its Receptor Splice Variant CXCR3-B in MDA-MB-435 and MCF-7 Cells: Relevance for the Development of Human Breast Cancer

Datta, Dipak; Flaxenburg, Jesse A.; Laxmanan, Sreenivas; Geehan, Christopher; Grimm, Martin; Waaga-Gasser, Ana Maria; Briscoe, David M.; Pal, Soumitro

doi:10.1158/0008-5472.can-05-4345

Cited by 145 publications

(165 citation statements)

References 47 publications

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“…CXCR3 has two splice variants with completely opposite functions in different cell types; CXCR3-A promotes cell proliferation and migration, whereas CXCR3-B inhibits these processes. 15,32 In our study, we found that the expression of CXCR3-A was markedly increased, whereas that of CXCR3-B was low in human CRC cell lines. In addition, we found that CXCL4, specific ligand for CXCR3-B, did not change the migratory and proliferative responses of HT29 cells (data not shown).…”

Section: Discussionmentioning

confidence: 47%

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The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Murakami

Kawada

Iwamoto

et al. 2012

Intl Journal of Cancer

113

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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: Discussionmentioning

confidence: 47%

“…[6][7][8][9][13][14][15] In CRC, it was reported that CXCR3 expression is upregulated in metastatic colon cancer cells, but not in their primary lesions, and that the CXCL10/CXCR3 axis…”

mentioning

confidence: 99%

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Murakami

Kawada

Iwamoto

et al. 2012

Intl Journal of Cancer

113

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“…4). 13,24 CXCL9 and CXCL10, the two most upregulated genes in our analysis, both have important pro-tumor roles [114][115][116][117] and can both be activated by the transcription factor NF-kb, as suggested in our model (Fig. 4).…”

Section: Cross-talk Between Transcription Factors Cytokines and Aqpssupporting

confidence: 59%

Role of aquaporins in cell proliferation: What else beyond water permeability?

2016

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In addition to the extensive data demonstrating the importance of mammalian AQPs for the movement of water and some small solutes across the cell membrane, there is now a growing body of evidence indicating the involvement of these proteins in numerous cellular processes seemingly unrelated, at least some of them in a direct way, to their canonical function of water permeation. Here, we have presented a broad range of evidence demonstrating that these proteins have a role in cell proliferation by various different mechanisms, namely, by allowing fast cell volume regulation during cell division; by affecting progression of cell cycle and helping maintain the balance between proliferation and apoptosis, and by crosstalk with other cell membrane proteins or transcription factors that, in turn, modulate progression of the cell cycle or regulate biosynthesis pathways of cell structural components. In the end, however, after discussing all these data that strongly support a role for AQPs in the cell proliferation process, it remains impossible to conclude that all these other functions attributed to AQPs occur completely independently of their water permeability, and there is a need for new experiments designed specifically to address this interesting issue.

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“…Considerably less is known about the role of the CXCR3 receptor, which binds the ligands CXCL9, CXCL10, and CXCL11. Human and murine breast cancer cell lines express CXCR3 mRNA and protein (3,6,16). CXCR3 has also been detected on melanoma, ovarian and renal cell carcinoma, B-cell leukemia, prostate, and colorectal cell lines (17 -22).…”

Section: Discussionmentioning

confidence: 99%

“…Others have reported that CXCR3 was detected in a small series of breast malignancies (6). Nothing was known, however, about the relationship of CXCR3 in breast cancer to clinical behavior.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model

Norsworthy²,

Kundu³

et al. 2009

Molecular Cancer Therapeutics

128

111

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Breast tumor cells express the chemokine receptor CXCR3, which binds the ligands CXCL9, CXCL10, and CXCL11. CXCR3 and other chemokine receptors may mediate tumor metastasis by supporting migration of tumor cells to sites of ligand expression including the lymph nodes, lungs, and bone marrow. We examined the relationship of CXCR3 expression to clinical outcome in 75 women diagnosed with early-stage breast cancer. We detected CXCR3 in malignant epithelium from all tumors. Twelve percent were weakly positive and 64% had moderate levels of CXCR3. Strong CXCR3-positive staining was observed in 24% of tumors. Kaplan-Meier survival curves showed that high CXCR3 expression was associated with poorer overall survival; the unadjusted hazard ratio was 1.56 and it was marginally significant (P = 0.07). When interactions between lymph node status and CXCR3 were considered, the adjusted hazard ratio for CXCR3 was 2.62 (P = 0.02) for women with nodenegative disease at diagnosis, whereas the hazard ratio for CXCR3 was not significant for those with node-positive disease. CXCR3 gene silencing inhibited lung colonization and spontaneous lung metastasis from mammary glandimplanted tumors in a murine model. The size or growth rate of the locally growing tumors was not affected. The antimetastatic effect of CXCR3 gene silencing was compromised in mice depleted of Natural Killer cells or with mutations in IFN-;, suggesting that the role of CXCR3 is not simply to mediate tumor cell trafficking. These studies support the continued examination of CXCR3 as a potential therapeutic target in patients with breast cancer. [Mol Cancer Ther 2009;8(3):490 -8]

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Ras-induced Modulation of CXCL10 and Its Receptor Splice Variant CXCR3-B in MDA-MB-435 and MCF-7 Cells: Relevance for the Development of Human Breast Cancer

Cited by 145 publications

References 47 publications

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Role of aquaporins in cell proliferation: What else beyond water permeability?

CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model

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