Embryonic Protein Nodal Promotes Breast Cancer Vascularization

Quail, Daniela F.; Walsh, Logan A.; Findlay, Scott D.; Moreno, Juan Carlos Alvarez; Fung, Laura; Ablack, Amber; Lewis, John D.; Done, Susan J.; Hess, David A.; Postovit, Lynne-Marie

doi:10.1158/0008-5472.can-11-3951

Cited by 35 publications

(49 citation statements)

References 44 publications

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“…It also highlights the potential for targeting Nodal in breast cancer. Adding to this information, another study examined vascularization in breast cancer samples and found that levels of Nodal protein within tumors correlated with microvascular density as assessed by CD31 staining [161]. In vitro analysis in this study revealed that Nodal regulated factors associated with angiogenesis such as VEGF and PDGF in breast cancer cells.…”

Section: Nodal and Cancermentioning

confidence: 86%

Plasticity underlies tumor progression: role of Nodal signaling

Bodenstine

Chandler

Seftor

et al. 2016

Cancer Metastasis Rev

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The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its re-expression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition.

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Section: Nodal and Cancermentioning

confidence: 86%

Plasticity underlies tumor progression: role of Nodal signaling

Bodenstine

Chandler

Seftor

et al. 2016

Cancer Metastasis Rev

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“…[21][22][23] Studies have correlated the altered expression of Nodal with the development, progression, and aggressiveness of various cancers. 7,[24][25][26] We have previously observed reduced Cripto messenger RNA (mRNA) levels in endometriotic lesions as well as in the eutopic endometrium of affected women. 3,27 However, no previous study has evaluated the protein levels of Nodal and Cripto and the SMADs involved in their signaling pathway in women with endometriosis.…”

Section: Introductionmentioning

confidence: 99%

Expression of Nodal, Cripto, SMAD3, Phosphorylated SMAD3, and SMAD4 in the Proliferative Endometrium of Women With Endometriosis

et al. 2015

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Background: Nodal is a growth factor of the transforming growth factor b superfamily that is expressed in high turnover tissues, such as the human endometrium, and in several malignancies. The effects of Nodal are modulated by the coreceptor Cripto and mediated by SMAD proteins. This study evaluated the gene and protein expression of Nodal, Cripto, total and phosphorylated (p) SMAD3, and SMAD4 in the proliferative endometrium of women with and without endometriosis. Method: Total RNA was isolated and complementary DNA synthesized from eutopic endometrium of women with (n ¼ 15) and without (n ¼ 12) endometriosis, followed by quantitative real-time polymerase chain reaction (PCR) to evaluate the gene expression of Nodal, Cripto, SMAD3, and SMAD4. Western blot was used to evaluate the protein levels of Nodal and Cripto, and immunohistochemistry was performed to localize SMAD3, pSMAD3, and SMAD4. Results: Although Nodal expression was unchanged in women with endometriosis, real-time PCR indicated lower gene expression of Cripto (fold change 0.27, P < .05) in the endometriosis group. This difference, however, was not maintained at protein expression level as assessed by Western blot. The immunostaining of total SMAD3 was reduced in the endometriosis group (P < .01), but the localization of pSMAD3 and the nuclear staining of SMAD4 were unchanged. Conclusion: These findings suggest that the Nodal signaling pathway has subtle changes in the endometrium of women with endometriosis, but this imbalance may not cause functional damage as it seems not to affect the nuclear expression of SMAD4.

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“…These data indicate that higher levels of Nodal are found within TNBC even when compared to invasive receptor positive tumors (summarized in Table 1), and are in agreement with studies that have reported correlations with Nodal expression and aggressive cancer-related characteristics. 13,15,[18][19][20][21][22][23] Collectively, our results demonstrate the robust presence of Nodal in TNBC samples, representing a potential new target for this disease.…”

Section: Resultsmentioning

confidence: 76%

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

et al. 2016

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Triple-negative breast cancer (TNBC) represents an aggressive cancer subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The independence of TNBC from these growth promoting factors eliminates the efficacy of therapies which specifically target them, and limits TNBC patients to traditional systemic neo/ adjuvant chemotherapy. To better understand the growth advantage of TNBC -in the absence of ER, PR and HER2, we focused on the embryonic morphogen Nodal (associated with the cancer stem cell phenotype), which is re-expressed in aggressive breast cancers. Most notably, our previous data demonstrated that inhibition of Nodal signaling in breast cancer cells reduces their tumorigenic capacity. Furthermore, inhibiting Nodal in other cancers has resulted in improved effects of chemotherapy, although the mechanisms for this remain unknown. Thus, we hypothesized that targeting Nodal in TNBC cells in combination with conventional chemotherapy may improve efficacy and represent a potential new strategy. Our preliminary data demonstrate that Nodal is highly expressed in TNBC when compared to invasive hormone receptor positive samples. Treatment of Nodal expressing TNBC cell lines with a neutralizing anti-Nodal antibody reduces the viability of cells that had previously survived treatment with the anthracycline doxorubicin. We show that inhibiting Nodal may alter response mechanisms employed by cancer cells undergoing DNA damage. These data suggest that development of therapies which target Nodal in TNBC may lead to additional treatment options in conjunction with chemotherapy regimens -by altering signaling pathways critical to cellular survival.

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Embryonic Protein Nodal Promotes Breast Cancer Vascularization

Cited by 35 publications

References 44 publications

Plasticity underlies tumor progression: role of Nodal signaling

Plasticity underlies tumor progression: role of Nodal signaling

Expression of Nodal, Cripto, SMAD3, Phosphorylated SMAD3, and SMAD4 in the Proliferative Endometrium of Women With Endometriosis

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

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