Significance of Plasma Cytokine Levels in Melanoma Patients With Histologically Negative Sentinel Lymph Nodes

Porter, Geoffrey A.; Abdalla, Joseph; Lu, Mason; Smith, Shannon E.; Montgomery, Diane; Grimm, Elizabeth A.; Ross, Merrick I.; Mansfield, Paul F.; Gershenwald, Jeffrey E.; Lee, Jeffrey E.

doi:10.1007/s10434-001-0116-3

Cited by 27 publications

(20 citation statements)

References 32 publications

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“…In general, these results are consistent with studies of others that have revealed Th2 cytokine skewing in cancer patients [17]. For example, serum IL-6 levels have been demonstrated to correlate with disease status of gastric cancer, although whether there was a concurrent decrease in Th1 cytokines was not determined [18].…”

Section: Discussionsupporting

confidence: 92%

Incomplete Th2 skewing of cytokines in plasma of patients with squamous cell carcinoma of the head and neck

2003

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Section: Discussionsupporting

confidence: 92%

Incomplete Th2 skewing of cytokines in plasma of patients with squamous cell carcinoma of the head and neck

2003

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“…Activation of macrophages is also produced by cytokines released by stimulated lymphocytes, and IFN-␥ has been shown to activate macrophages to become tumoricidal (38). However, in this study, IFN-␥ in the regional lymph node did not increase after cancer cell inoculation or NAAI pretreatment for macrophage activation, and an inadequate IFN-␥ response is also found in the sentinel lymph node of melanoma-bearing patients (39). IL-12 has been found to enhance IFN-␥ production and activate T cells, resulting in tumor growth inhibition (40), but in the present study, IL-12 did not up-regulate IFN-␥ after cancer cell inoculation.…”

Section: Discussioncontrasting

confidence: 71%

Limited Capability of Regional Lymph Nodes to Eradicate Metastatic Cancer Cells

et al. 2004

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The capacity of lymph nodes to eradicate cancer is a controversial issue. The purpose of this study was to determine the interplay between tumor growth and host resistance at early stages of lymph node metastasis. A metastasis model was made in the rat mesenteric lymph node, and migration of cancer cells was visualized in vivo. The lymph node was removed for histologic analysis and cytokine measurement. Migrant cancer cells were initially arrested in the marginal sinus. After an initial increase, the number of cancer cells in the marginal sinus declined until 48 hours after inoculation. Germinal centers and lymphoid cells in the medulla proliferated before 48 hours. ED3؉ macrophages incorporated apoptotic cancer cells, but significant cancer proliferation occurred after 4 days. Lymph nodes depleted of macrophages were massively invaded by cancer cells. Tumor necrosis factor ␣ and interleukin (IL)-1␤ in the nodes transiently increased after 1 hour and 3 hours, respectively, and were expressed in ED3 ؉ and ED2 ؉ macrophages, respectively. These changes were followed by a transient increase in IL-2. Interferon-␥ and IL-12 did not increase during the early stages of metastasis, but they decreased after 48 hours. In conclusion, the marginal sinus constitutes a mechanical barrier against cancer cell passage. Early pathological manifestations in the regional lymph node are consistent with those in cancer patients with improved survival. Parasinus macrophages play a role in the transient antimetastatic capability of the node, and cytokines secreted by these cells increased at the early stages of metastasis. Deterioration of cytokine induction may be responsible for subsequent cancer proliferation.

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“…In support of these findings, distinct aggressive tumor phenotypes expressing high IFN-γ predict poor patient survival (27). Also, elevated serum IFN-γ predicted cancer recurrence and reduced disease-free survival in melanoma patients (28). Because INF-γ up-regulates NOS2 in aggressive breast cancer cells, we explored potential mechanistic effects linking IFN-γ signaling with elevated NOS2 tumor expression that predicted poor breast cancer specific survival in ER − patients (4).…”

Section: Discussionmentioning

confidence: 97%

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Heinecke¹,

Ridnour²,

Cheng³

et al. 2014

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

164

151

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Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance our mechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER − and ER + breast cancer cells and examined downstream NO-dependent effects. Herein, we show that up-regulation of NOS2 occurs in response to hypoxia, serum withdrawal, IFN-γ, and exogenous NO, consistent with a feed-forward regulation of NO production by the tumor microenvironment in breast cancer biology. Moreover, we found that key indicators of an aggressive cancer phenotype including increased S100 calcium binding protein A8, IL-6, IL-8, and tissue inhibitor matrix metalloproteinase-1 are up-regulated by these NOS2 stimulants, whereas inhibition of NOS2 in MDA-MB-231 breast cancer cells suppressed these markers. Moreover, NO altered cellular migration and chemoresistance of MDA-MB-231 cells to Taxol. Most notably, MDA-MB-231 tumor xenographs and cell metastases from the fat pad to the brain were significantly suppressed by NOS2 inhibition in nude mice. In summary, these results link elevated NOS2 to signals from the tumor microenvironment that arise with cancer progression and show that NO production regulates chemoresistance and metastasis of breast cancer cells.I nflammation is a major component of the tumor microenvironment and a driving force in cancer initiation, promotion, and progression (1-3). Epithelial cancers express markers of inflammation that promote disease progression and drug resistance through evasion of cell death pathways and increased tumor metastasis. Rapid cancer growth leads to tumor hypoxia and nutrient deprivation, which promotes chronic inflammatory feed-forward signaling and selection of resistant tumors that are clinically challenging and sometimes untreatable.Several proinflammatory proteins such as COX2, NF-κB, IL-6, IL-8, S100 calcium binding protein A8 (S100A8), and VEGF are markers of chronic inflammation in the tumor microenvironment. In addition, these proinflammatory mediators directly correlate with inducible nitric oxide synthase (NOS2), which is an emerging biomarker of aggressive tumors that predicts poor survival in patients with elevated tumor NOS2 expression (4-8). These and other clinical studies warrant an improved mechanistic understanding of intratumoral NOS2 regulation and endogenous NO production, which may be therapeutically beneficial.Toward this end, our laboratory and others have used NO donors to study NO signaling in cancer. However, intratumoral NOS2 induction by components of the tumor microenv...

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Significance of Plasma Cytokine Levels in Melanoma Patients With Histologically Negative Sentinel Lymph Nodes

Cited by 27 publications

References 32 publications

Incomplete Th2 skewing of cytokines in plasma of patients with squamous cell carcinoma of the head and neck

Incomplete Th2 skewing of cytokines in plasma of patients with squamous cell carcinoma of the head and neck

Limited Capability of Regional Lymph Nodes to Eradicate Metastatic Cancer Cells

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

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