With increased knowledge in endothelial attachment and transcapillary migration, there is now a focus on inflammatory as well as non-inflammatory cell infiltrates and their contribution to cancer cell spread. Chemokines and certain of the larger cytokines may contribute to the migration of leukocytic and other cells into a tumor environment among their other properties. The chemokines now have a new nomenclature based on their chemical structure [
28], and extensive reviews have been published [
29]. In EOC, particularly in studies on ascites, substantial amounts of certain CC and CXC chemokines have been demonstrated, including CCL18 (PARC), CXCL8 (IL8), CCL2 (MCP1), and CCL3 (MIP1α) [
30] (Table
1). Transcripts for CCL4 (MIP1β), CCL5 (RANTES), CCL7 (MCP3) have been demonstrated in EOC cells [
31] CCL13, however, is produced by ascitic macrophages and cannot be induced in EOC cells [
30]. Chemokines and cytokines may have in common potent functional properties, such as chemotaxis and proangiogenesis, and typically have effects in proximity to cells producing them. Larger cytokine molecules, such as TGFβ, may also have chemotactic and proangiogenic effects. In advanced disease, tumor cells and other cells of nontumor origin, can contribute to chemokine production. CXCL8 (IL8) is very pleiotropic and is constitutively produced or induced by both hematogenous and non-hematogenous cells and by hypoxia. We found that CXCL8 was overexpressed on the peritoneal stroma along with other network genes and appears to be a pivotal chemokine with substantial interactions at the transcript level with genes that are involved in inflammation, angiogenesis, and chemotaxis [
27,
32]. Receptors for the chemokines are expressed on a variety of hematogenous cells, including T cells and macrophages [
33]. Of interest, CXCR4, the receptor for CXCL12 (SDF1), appears to be selectively expressed on EOC cells [
34] and may contribute to tumor cell migration. There is a lack of detectable change in expression of other chemokine receptors in response to cytokines, except for CCR2, the receptor for CCL2 and certain other CC chemokines, which appears to be downregulated on EOC ascitic macrophages [
35]. This effect may interfere with migration of macrophages away from the tumor site while contributing to a tumor-promoting environment [
35]. Unlike cytokines, many chemokines may exhibit more promiscuous binding to receptors. This may insure a regional effect through their redundancy.
Several cytokines have been detected in serum and ascites of EOC patients, including TGFβ isotypes, IL10, IL6, TNFα, CSF1 and IL1 [
19,
36,
37,
12,
38]. TGFβ isotypes are produced by EOC cells [
39] on mononuclear leukocytes, including CD14+DR- [
23] and T regulatory cells [
22]. TGFβ, in its activated form, was previously considered a tumor-inhibitory cytokine but its tumor-reactive properties appear to be more complex (Table
2). TGFβ also can have a tumor promoting effect in advanced cancer possibly through activation of cdk inhibitors that block the unbinding of the pRb/E2F transcripts [
40], and interference with TGFβ receptor binding mediated by H-Ras, as well as consequent to c-myc, its reaction with the E2F transcription factor complex [
40]. The signaling pathway of TGFβ within tumor cells may also be subverted due to mutations, or interactions with other cytokines. A TGFβ activation response might, however, prevail in the microenvironment where it may contribute to myofibroblast and endothelial cell chemotaxis, tumor adhesion, and suppression of adaptive and innate immunity [
41]. IL10 is also produced in association with EOC with a large contribution by CD14+DR- MO/MA, and these cells may function as immune regulatory cells. IL6 is expressed by EOC tumor cells as well as mesothelial cells and has been detected in the serum and ascites of EOC cells [
42‐
45]. A recent study has shown that IL6 and MCP production by submesothelial cells can be enhanced during abdominal surgery [
46]. IL6 also enhances tumor attachment and proliferation of tumor cells, most likely through the PI 3-K activation mechanisms, and can interfere with the maturation of MO/MA to DC [
44,
45]. This finding might contribute to the large number of functionally immature DC in the ascitic fluid and absent levels of IL12, a product of DC maturation [
47,
48] (and C Butts' unpublished observations).
Table 1
Chemokines/Receptors in EOC
CCL2 (MCP1) *+ | CCR2 | Activated T, Monocytes, DC, Basophils | CD8+ T cells, CD68+ MA ↓ on ascitic MA |
CCL3 (MIP1α)*+ | CCR2 | Activated T, NK, MO, Eosinophils | |
CCL4 (MIP1β)*+ | Unknown | | |
CCL5 (RANTES) * | CCR2 | Activated T, NK, MO, Eosinophils | |
CCL7 (MCP3) + | CCR2 | | |
CCL18 (PARC) + | Unknown | | MA produced but not induced in EOC cells |
CXCL8 (IL8) *+ | CXCR1, CXCR2 | Neutrophils, Resting T | |
CXCL12 (SDF1) *+ | CXCR4 | Neutrophils, Resting T, Activated T, B, MO | CXCR4 preferentially expressed on EOC cells |
Table 2
Dual Effects of Cytokines on Tumor/Tumor Microenvironment
• TGFβ + TGFβ RIII → TGFβ - RII + RI heterodimer → TGFβ RI - P + SMADs → SMAD - P → nucleus → initiates transcription • TGFβ → in repression cell cycle genes or activation • Repression involves activation of cycle dependent kinase inhibitors, blocks unbinding of pRb/E2F transcripts • Other interactions include: H-Ras (↓ RI & ↑ RII); C-Myc (stimulates proliferation by repressing cdk inhibitors) associates w/E2F transcript factor complex • TGFβ effect negated by disruption of signal pathway • Alterations to the microenviroment Tumor adhesion Endothelial chemotaxis (proangiogenic) Myofibroblast chemotaxis • Immunosuppressive Effects Adaptive ↓ MHC expression (targeting) ↓ Costimulatory Ag expression by DC Blocks pre CTL → CTL Suppresses TH1 cells - Shift to TH2 Induces apoptosis Suppresses proliferative response to APCs Innate Cells Inhibits NK & MA activation | • ↑ TuC attachment migration • Immune modulation (T-cell ↑) • Interferes w/MA maturation to DC • Proliferation thru P13-K activation
IL10
• ↓ MHC expression on TC • ↓ Costimulatory Ag expression • Suppress cytotoxic T-cell activation • Inhibits IFNγ production • Inhibits T-cell production |