Active Roles of Tumor Stroma in Breast Cancer Metastasis

Khamis, Zahraa I.; Sahab, Ziad J.; Sang, Qing‐Xiang Amy

doi:10.1155/2012/574025

Cited by 67 publications

(63 citation statements)

References 95 publications

(125 reference statements)

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“…Emerging research is illuminating the underlying cellular and molecular events controlling the metastatic cascade from onset to colonization. Now it is defined that a reciprocal interplay between tumor cells, stromal cells and the ECM mediate metastasis in epithelial cancers (Khamis et al, 2012). The essential components of metastatic niches include ECM proteins, secreted enzymes, growth factors, cytokines and other molecules that carry information to cancer cells.…”

Section: Metastatic Nichesmentioning

confidence: 99%

“…Further, the stromal compartment contains various bone-marrow-derived cells (BMDCs) such as macrophages, mast cells, neutrophils, and lymphocytes recruited by the primary tumor cells to increase tumor cell migration, angiogenesis, and invasion. Observation of immune infiltrates at sites of focal disruptions of the myoepithelial cell layer in breast tissues suggests a potential role of these cells in tumor malignancy and metastatic spread (Khamis et al, 2012; Kuznetsov et al, 2012). Collective dissemination is a frequent mechanism for metastatic spread and whether the most invasive, keratin 14+ (K14+) expression in breast cancer cells regulate cell–cell adhesion, cell–matrix adhesion, and immune evasion (Cheung et al, 2013; Cheung et al, 2016).…”

Section: Metastatic Nichesmentioning

confidence: 99%

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Tumor Microenvironment Heterogeneity: Challenges and Opportunities

et al. 2017

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The tumor microenvironment (TME) has been recognized as an integral component of malignancies in breast and prostate tissues, contributing in confounding ways to tumor progression, metastasis, therapy resistance and disease recurrence. Major components of the TME are immune cells, fibroblasts, pericytes, endothelial cells, mesenchymal stroma/stem cells (MSCs), and extracellular matrix (ECM) components. Herein, we discuss the molecular and cellular heterogeneity within the TME and how this presents unique challenges and opportunities for treating breast and prostate cancers.

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Section: Metastatic Nichesmentioning

confidence: 99%

Section: Metastatic Nichesmentioning

confidence: 99%

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

et al. 2017

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“…Metastasis is the primary cause of breast cancer-related deaths; however, the molecular mechanisms underlying this process are still poorly understood. It has been well established that the tumor microenvironment plays an important role in breast cancer metastasis (3)(4)(5)(6). Tumor-associated macrophages (TAMs) make up the largest population of stromal cells that suppress antitumor immunity and foster tumor progression in mouse models of breast cancer (3,(6)(7)(8).…”

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confidence: 99%

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Chen

Zuo

Xiong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

325

280

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Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor-macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor-macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.reast cancer is the most frequently diagnosed nonskin type of malignancy, and the second leading cause of cancer-related death in women. The 5-y survival rate is 89% in patients who have primary breast cancer, whereas the medium survival of patients with metastatic breast cancer is only 1-2 y (1, 2). Metastasis is the primary cause of breast cancer-related deaths; however, the molecular mechanisms underlying this process are still poorly understood. It has been well established that the tumor microenvironment plays an important role in breast cancer metastasis (3-6). Tumor-associated macrophages (TAMs) make up the largest population of stromal cells that suppress antitumor immunity and foster tumor progression in mouse models of breast cancer (3,(6)(7)(8). TAMs also promote metastasis and correlate with poor prognosis in patients with breast cancer (7, 9). Conversely, TAM functions are also tightly regulated by tumor cells (10, 11). However, the mechanisms underlying this reciprocal regulation between cancer cells and macrophages during metastasis remain elusive.Macrophages are heterogeneous immune cells that can exhibit distinct functions and phenotypes depending on different microenvironment signals (9, 12). They can be broadly divided into classically activated (M1) and alternatively activated (M2) macrophages, the latter of which generally display promalignancy activity (9, 12). In solid tumors, TAMs are usually biased toward M2 (9). Due to hypoxia and glycolytic cancer cell metabolism, the tumor environment is usually acidic, which affects tumor progression by acting on both cancer cells and stromal cells, including macrophages (10,13,14). A recent study shows that cancer cell-derived lactate can educate macrophages to functional TAMs, which, in turn, promotes tumor growth (14). Nonetheless, how lactate activation of TAMs affects cancer metastasis is poorly understood. Importantly, the molecular basis by which macrophages sense and respond t...

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“…Some studies reported cytoplasmic positivity for ALDH1 expression in tumor cells only [6,11,12], and some studies detected both cytoplasmic positivity of tumor cells and stromal positivity for ALDH1 expression [15,24,25]. Since tumor stromal cells are known to be involved in tumor growth and metastasis [21,33], differences in the distribution and characteristics of cytoplasmic cellular or stromal expression of ALDH1 need to be elucidated to better understand the exact role of ALDH1 expression in breast cancer. A few previous reports have analyzed the implications of cellular and stromal expression.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor stromal cells are a part of the local microenvironment, which includes myoepithelial cells, fibroblasts, myofibroblasts, endothelial cells, and inflammatory cells. The tumor stroma is known to play a role in breast cancer metastasis [21]. However, few studies have evaluated the prognostic value and related characteristics of both tumor cell and stromal expression.…”

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confidence: 99%

Association of aldehyde dehydrogenase 1 expression and biologically aggressive features in breast cancer

Kang¹,

Jung

Woo³

et al. 2014

neo

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Aldehyde dehydrogenase 1 (ALDH1) has been regarded as a breast cancer stem cell marker. Several studies have reported that ALDH1 expression is associated with poor prognosis in breast cancer. We aimed, therefore, to determine the prognostic value of ALDH1 expression and its association with several biomarkers in breast cancer tissue using immunohistochemistry. Furthermore, we investigated the characteristics of and differences between cellular and stromal expression of ALDH1. We performed tissue microarray (TMA) analysis of 425 breast cancer tissue samples collected during surgery. Immunohistochemical staining was then performed to measure the expression of ALDH1 and other breast cancer biomarkers. Statistical analysis of the relationship between ALDH1 expression and clinicopathologic characteristics was performed for 390 TMA samples. We found that ALDH1 was expressed in 71 cases (18.2%) in the tumor cells and/or stroma. Of these cases, 38 (9.7%) showed ALDH1 expression in tumor cells and 38 (9.7%) showed ALDH1 expression in the stroma. ALDH1 expression was significantly associated with markers of a poor prognosis, such as young age, estrogen receptor negativity, progesterone receptor negativity, a high histological grade, and a high Ki-67 index. However, ALDH1 expression was not associated with p53, transforming growth factor-beta, Gli-1, YKL-40, or sonic hedgehog expression status. With regard to the expression site, the clinical characteristics did not differ between cases of cellular expression and those of stromal expression. However, ALDH1 expression in tumor cells was correlated with hormone receptor status, histological grade, molecular subtype, epidermal growth factor receptor expression status, and cytokeratin 5/6 expression status while stromal expression of ALDH1 was only correlated with hormone receptor status. Overall, these findings suggest that ALDH1 expression in tumor tissue is associated with a biologically aggressive phenotype.

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Active Roles of Tumor Stroma in Breast Cancer Metastasis

Cited by 67 publications

References 95 publications

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Association of aldehyde dehydrogenase 1 expression and biologically aggressive features in breast cancer

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