Abstract: Cancer cells are distinguished by several distinct characteristics, such as self-sufficiency in growth signal, resistance to growth inhibition, limitless replicative potential, evasion of apoptosis, sustained angiogenesis, and tissue invasion and metastasis. Tumor cells acquire these properties due to the dysregulation of multiple genes and associated cell signaling pathways, most of which are linked to inflammation. For that reason, rationally designed drugs that target a single gene product are unlikely to be of use in preventing or treating cancer. Moreover, targeted drugs can cause serious and even life-threatening side effects. Therefore, there is an urgent need for safe and effective promiscuous (multitargeted) drugs. “Mother Nature” produces numerous such compounds that regulate multiple cell signaling pathways, are cost effective, exhibit low toxicity, and are readily available. One among these is tocotrienol, a member of the vitamin E family, which has exhibited anticancer properties. This review summarizes data from in vitro and in vivo studies of the effects of tocotrienol on nuclear factor-κB, signal transducer and activator of transcription (STAT) 3, death receptors, apoptosis, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hypoxia-inducible factor (HIF) 1, growth factor receptor kinases, and angiogenic pathways.
Kannappan R, et al. Tocotrienols fight cancer by targeting multiple cell signaling pathways. Genes & nutrition. 2012 Vol 7, Issue 1. Pp 43-52

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E.

Abstract: The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (γ and δ) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated “highly metabolized” T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.
Viola V et al. Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E. Genes & nutrition. 2012 Vol 7, Issue 1. Pp 29-41

Tocotrienols and breast cancer: the evidence to date.

Abstract: Breast cancer is the second most frequent cancer affecting women worldwide after lung cancer. The toxicity factor associated with synthetic drugs has turned the attention toward natural compounds as the primary focus of interest as anticancer agents. Vitamin E derivatives consisting of the well-established tocopherols and their analogs namely tocotrienols have been extensively studied due to their remarkable biological properties. While tocopherols have failed to offer protection, tocotrienols, in particular, α-, δ-, and γ-tocotrienols alone and in combination have demonstrated anticancer properties. The discovery of the antiangiogenic, antiproliferative, and apoptotic effects of tocotrienols, as well as their role as an inducer of immunological functions, not only reveals a new horizon as a potent antitumor agent but also reinforces the notion that tocotrienols are indeed more than antioxidants. On the basis of a transcriptomic platform, we have recently demonstrated a novel mechanism for tocotrienol activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicate a high affinity of specific forms of tocotrienols for ERβ, but not for ERα. Moreover, we have demonstrated that specific tocotrienols increase ERβ translocation into the nucleus which, in turn, activates the expression of estrogen-responsive genes (MIC-1, EGR-1 and Cathepsin D) in breast cancer cells only expressing ERβ cells (MDA-MB-231) and in cells expressing both ER isoforms (MCF-7). The binding of specific tocotrienol forms to ERβ is associated with the alteration of cell morphology, caspase-3 activation, DNA fragmentation, and apoptosis. Furthermore, a recently concluded clinical trial seems to suggest that tocotrienols in combination with tamoxifen may have the potential to extend breast cancer-specific survival.
Nesaretnam K, et al. Tocotrienols and breast cancer: the evidence to date. Genes & nutrition. 2012 Vol. 7 Issue 1 Pp 3-9

Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells.

Abstract: Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Identifying novel chemotherapeutic and chemopreventive approaches is critical in the prevention and treatment of cancers such as pancreatic cancer. Vitamin E succinate (VES) is a redox-silent analog of the fat-soluble vitamin alpha-tocopherol. In the present study, we explored the antiproliferative action of VES and its effects on inhibitor of apoptosis proteins in pancreatic cancer cells. We show that VES inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. Further, we demonstrate that VES downregulates the expression of survivin and X-linked inhibitor of apoptosis proteins. The apoptosis induced by VES was augmented by siRNA-mediated inhibition of survivin in PANC-1 cells. In summary, our results suggest that VES targets survivin signaling and induces apoptosis in pancreatic cancer cells.
Patacsil D et al. Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells. Genes & nutrition. 2012 Vol. 7 Issue 1 Pp 83-9

In the current study, we demonstrated that curcumin, EGCG, lovastatin, and their combinations can significantly reduce the viability and invasion capacity of esophageal cancer cells in vitro. Nevertheless, they were much less effective in vivo in nude mouse xenografts, especially curcumin and lovastatin individually. At the molecular level, these three agents individually or in combination inhibited the expression of phosphorylated Erk1/2, c-Jun, and COX-2 and induced caspase 3 expression in esophageal cancer cells in vitro. In nude mouse xenografts, the expression of p-Erk1/2 and COX-2 was downregulated by these three drugs, especially their combinations. We also analyzed the expression of phosphorylated Erk1/2 and COX-2 in tissue specimens from esophageal cancer patients. The data showed that 49.4% of esophageal cancers expressed phosphorylated Erk1/2 and that 77.6% of cancers expressed COX-2 protein. These data suggest that curcumin, EGCG, and lovastatin inhibit esophageal cancer cell growth in vitro and in nude mouse xenografts possibly through the suppression of phosphorylated Erk1/2, c-Jun and COX-2 expression.

Previous studies have shown the chemopreventive activity of EGCG in suppressing carcinogenesis in several organs, including the esophagus[29,34]. Molecularly, EGCG can suppress the mitotic signal transduction pathway, e.g., inhibit Erk1/2 phosphorylation and anti-AP-1 activity[38]. A recent study demonstrated that EGCG induced a concentration- and time-dependent reversal of hypermethylation of RAR-β2 in esophageal cancer cell lines, resulting in re-expression of RAR-β2[33]. Furthermore, curcumin has been shown to inhibit different cancers at the initiation, promotion, and progression stages in animal models[31,32,38]. Curcumin also suppressed growth and induced apoptosis in numerous types of cancer cells in vitro[38,39]. Although the defined mechanisms of its action require further study, its efficacy appears to be related to the induction of glutathione and glutathione-S-transferase activity, inhibition of lipid peroxidation and arachidonic acid metabolism, and suppression of oxidative DNA adduct formation[32,38,39]. Curcumin can inhibit the activation of NF-κB and the expression of c-Jun, c-Fos, c-Myc, Erk1/2, COX-2, PI3K, Akt, CDKs, and iNOS[31,35,38,39]. Curcumin was also able to suppress cigarette smoke-induced NF-κB activation and COX-2 expression in head and neck SCC and non-small-cell lung cancer cells[31,32]. In esophageal cancer, dietary curcumin can inhibit chemically-induced esophageal carcinogenesis in mice and rats[28,40]. In addition, the statin family of drugs has shown cancer chemopreventive effects[41]. Statins can trigger some tumor cells to undergo apoptosis in vitro and suppress tumor growth in vivo[30,37,41]. Statins also have an antimetastatic property, which is evident in their suppression of tumor cells invasiveness in Matrigel, as well as in animal experiments[42]. In addition, statins, especially at high concentrations, can inhibit capillary tube formation by endothelial cells in vitro and in vivo[33,44]. The effects of statins are thought to be mediated through inhibition of Ras and RhoA activity[41]. Based on these previous studies and reports, we determined the effects of their combinations on suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts by targeting the RAR-β2/Erk1/2/AP1/COX-2 pathway[3]. Indeed, our current study has demonstrated the effects of their combinations in vitro. Molecularly, these three agents were able to regulate the expression of this gene pathway in vitro and in vivo in nude mice. Nevertheless, individually curcumin and lovastatin had no effect on tumor formation and growth in nude mice, even when the highest dose possible was used. This may be due to the bioavailability of curcumin and the induction of COX-2 expression by high dose lovastatin, reported previously[30,39]. However, the current study did not show the induction of COX-2 expression by high dose lovastatin in esophageal cancer in vitro and in nude mice, similar to that seen in prostate cancer[30].

However, there are some limitations in the current study. Firstly, we showed that these three drugs regulated gene expression of the RAR-β2/Erk1/2/AP1/COX-2 pathway, however, previous studies also showed that as chemoprevention agents, these drugs target multiple genes and their pathways in different cancers. Thus, further study is needed to determine the mechanisms of action of these drugs in human cancers. Furthermore, we used established esophageal cancer cell lines to determine the chemopreventive effects of these agents in this study, the results of which may be quite different in comparison to those in premalignant cells in vivo. The xenograft assay tested the effects of these agents in suppressing tumor initiation and growth, but not tumor development per se, although the xenograft assay did test the bioavailability of these agents in vivo. In addition, we did not test whether the doses of these three agents are clinically achievable, and to reduce costs, we utilized a single dose of each agent and their combinations.
Source:
Ye F, Zhang G-H, Guan B-X, Xu X-C. To determine the effects of curcumin, (-)-epigallocatechin-3-gallate (EGCG), lovastatin, and their combinations on inhibition of esophageal cancer. World journal of gastroenterology: WJG. 2012 Vol. 18 Issue 2. Pp 126-35
Referencs:
29. Li ZG, Shimada Y, Sato F, Maeda M, Itami A, Kaganoi J, Komoto I, Kawabe A, Imamura M. Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats. Int J Oncol. 2002;21:1275–1283. [PubMed]
30. Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S, Zhang H, Cao L, Ajani JA, Xu XC. Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention. Carcinogenesis. 2005;26:785–791. [PubMed]
31. Aggarwal S, Takada Y, Singh S, Myers JN, Aggarwal BB. Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling. Int J Cancer. 2004;111:679–692. [PubMed]
32. Shishodia S, Potdar P, Gairola CG, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis. 2003;24:1269–1279. [PubMed]
33. Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang CS. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 2003;63:7563–7570. [PubMed]
34. Wang ZY, Wang LD, Lee MJ, Ho CT, Huang MT, Conney AH, Yang CS. Inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by green and black tea. Carcinogenesis. 1995;16:2143–2148. [PubMed]
35. Rafiee P, Nelson VM, Manley S, Wellner M, Floer M, Binion DG, Shaker R. Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs, and NF-kappaB. Am J Physiol Gastrointest Liver Physiol. 2009;296:G388–G398. [PubMed]
36. O’Sullivan-Coyne G, O’Sullivan GC, O’Donovan TR, Piwocka K, McKenna SL. Curcumin induces apoptosis-independent death in oesophageal cancer cells. Br J Cancer. 2009;101:1585–1595. [PMC free article] [PubMed]
37. Ogunwobi OO, Beales IL. Statins inhibit proliferation and induce apoptosis in Barrett’s esophageal adenocarcinoma cells. Am J Gastroenterol. 2008;103:825–837. [PubMed]
38. Conney AH. Enzyme induction and dietary chemicals as approaches to cancer chemoprevention: the Seventh DeWitt S. Goodman Lecture. Cancer Res. 2003;63:7005–7031. [PubMed]
39. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003;23:363–398. [PubMed]
40. Ushida J, Sugie S, Kawabata K, Pham QV, Tanaka T, Fujii K, Takeuchi H, Ito Y, Mori H. Chemopreventive effect of curcumin on N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats. Jpn J Cancer Res. 2000;91:893–898. [PubMed]
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43. Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation. 2002;105:739–745. [PubMed]
44. Vincent L, Chen W, Hong L, Mirshahi F, Mishal Z, Mirshahi-Khorassani T, Vannier JP, Soria J, Soria C. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett. 2001;495:159–166. [PubMed]

Herb Group: (60-90% flavones w/w)
Huai Shan Yao (Dioscorea villosa), xu duan (Dipsacus asper), balm of gilead bud (Populus balsamifera), bakuchi seed (Cymopsis psoralidoides), chan shan (Dichroa febrifuga), di fu zi (Kochia scoparia), huang shui qie (Solanum xanthocarpum), hu zhang (Polugonum Cuspidatum), da hui xiang (?) (Terminalia arjuna), babul chall bark (Acacia Arabica), Sweet Myrrh (Acacia farnesiana) zhu ye (?) (Phyllanthus niruri), Garcinia fruit (Garcinia Cambogia), Vitex (Vitex agnus-castus), Dragons Blood (Calamus draco), rou dou kou (Myristica fragans), White sage (Salvia apian), red sandal wood (Pterocarpus santalinu)

Mazzio E, Soliman K. Nutraceutical Composition and Method of use for treatment / prevention of cancer 2007 US patent 2007/0248693.

References:
Hughes KS, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer. 2010 ASCO Annual Meeting. Oral Abstract Session, Breast Cancer – Local-Regional and Adjuvant Therapy. J Clin Oncol 28:15s, 2010 (suppl; abstr 507)
Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N. Engl. J. Med. 2004;351(10):971-977.
Perez, Carlos and Brady, Luther, eds. Principles and Practice of Radiation Oncology, Philadelphia: LWW, 4th ed., 2004, p. 1371.

The discovery turns standard medical practice on its head. Surgeons have been removing lymph nodes from under the arms of breast cancer patients for 100 years, believing it would prolong women’s lives by keeping the cancer from spreading or coming back.
Now, researchers report that for women who meet certain criteria — about 20 percent of patients, or 40,000 women a year in the United States — taking out cancerous nodes has no advantage. It does not change the treatment plan, improve survival or make the cancer less likely to recur. And it can cause complications like infection and lymphedema, a chronic swelling in the arm that ranges from mild to disabling.
Removing the cancerous lymph nodes proved unnecessary because the women in the study had chemotherapy and radiation, which probably wiped out any disease in the nodes, the researchers said. Those treatments are now standard for women with breast cancer in the lymph nodes, based on the realization that once the disease reaches the nodes, it has the potential to spread to vital organs and cannot be eliminated by surgery alone.

Experts say that the new findings, combined with similar ones from earlier studies, should change medical practice for many patients. Some centers have already acted on the new information. Memorial Sloan-Kettering Cancer Center in Manhattan changed its practice in September, because doctors knew the study results before they were published. But more widespread change may take time, experts say, because the belief in removing nodes is so deeply ingrained.
“This is such a radical change in thought that it’s been hard for many people to get their heads around it,” said Dr. Monica Morrow, chief of the breast service at Sloan-Kettering and an author of the study, which is being published Wednesday in The Journal of the American Medical Association. The National Cancer Institute paid for the study.
Doctors and patients alike find it easy to accept more cancer treatment on the basis of a study, Dr. Morrow said, but get scared when the data favor less treatment.

The new findings are part of a trend to move away from radical surgery for breast cancer. Rates of mastectomy, removal of the whole breast, began declining in the 1980s after studies found that for many patients, survival rates after lumpectomy and radiation were just as good as those after mastectomy.
The trend reflects an evolving understanding of breast cancer. In decades past, there was a belief that surgery could “get it all” — eradicate the cancer before it could spread to organs and bones. But research has found that breast cancer can begin to spread early, even when tumors are small, leaving microscopic traces of the disease after surgery.
The modern approach is to cut out obvious tumors — because lumps big enough to detect may be too dense for drugs and radiation to destroy — and to use radiation and chemotherapy to wipe out microscopic disease in other places.
But doctors have continued to think that even microscopic disease in the lymph nodes should be cut out to improve the odds of survival. And until recently, they counted cancerous lymph nodes to gauge the severity of the disease and choose chemotherapy. But now the number is not so often used to determine drug treatment, doctors say. What matters more is whether the disease has reached any nodes at all. If any are positive, the disease could become deadly. Chemotherapy is recommended, and the drugs are the same, no matter how many nodes are involved.

The new results do not apply to all patients, only to women whose disease and treatment meet the criteria in the study.
The tumors were early, at clinical stage T1 or T2, meaning less than two inches across. Biopsies of one or two armpit nodes had found cancer, but the nodes were not enlarged enough to be felt during an exam, and the cancer had not spread anywhere else. The women had lumpectomies, and most also had radiation to the entire breast, and chemotherapy or hormone-blocking drugs, or both.
The study, at 115 medical centers, included 891 patients. Their median age was in the mid-50s, and they were followed for a median of 6.3 years.
After the initial node biopsy, the women were assigned at random to have 10 or more additional nodes removed, or to leave the nodes alone. In 27 percent of the women who had additional nodes removed, those nodes were cancerous. But over time, the two groups had no difference in survival: more than 90 percent survived at least five years. Recurrence rates in the armpit were also similar, less than 1 percent. If breast cancer is going to recur under the arm, it tends to do so early, so the follow-up period was long enough, the researchers said.

One potential weakness in the study is that there was not complete follow-up information on 166 women, about equal numbers from each group. The researchers said that did not affect the results. A statistician who was not part of the study said the missing information should have been discussed further, but probably did not have an important impact.
It is not known whether the findings also apply to women who do not have radiation and chemotherapy, or to those who have only part of the breast irradiated. Nor is it known whether the findings could be applied to other types of cancer.
The results mean that women like those in the study will still have to have at least one lymph node removed, to look for cancer and decide whether they will need more treatment. But taking out just one or a few nodes should be enough.
Dr. Armando E. Giuliano, the lead author of the study and the chief of surgical oncology at the John Wayne Cancer Institute at St. John’s Health Center in Santa Monica, Calif., said: “It shouldn’t come as a big surprise, but it will. It’s hard for us as surgeons and medical oncologists and radiation oncologists to accept that you don’t have to remove the nodes in the armpit.”
Dr. Grant W. Carlson, a professor of surgery at the Winship Cancer Institute at Emory University, and the author of an editorial accompanying the study, said that by routinely taking out many nodes, “I have a feeling we’ve been doing a lot of harm.”

Indeed, women in the study who had the nodes taken out were far more likely (70 percent versus 25 percent) to have complications like infections, abnormal sensations and fluid collecting in the armpit. They were also more likely to have lymphedema.
But Dr. Carlson said that some of his colleagues, even after hearing the new study results, still thought the nodes should be removed.
“The dogma is strong,” he said. “It’s a little frustrating.”
Eventually, he said, genetic testing of breast tumors might be enough to determine the need for treatment, and eliminate the need for many node biopsies.
Two other breast surgeons not involved with the study said they would take it seriously.
Dr. Elisa R. Port, the chief of breast surgery at Mount Sinai Medical Center in Manhattan, said: “It’s a big deal in the world of breast cancer. It’s definitely practice-changing.”
Dr. Alison Estabrook, the chief of the comprehensive breast center at St. Luke’s-Roosevelt hospital in New York said surgeons had long been awaiting the results.

“In the past, surgeons thought our role was to get out all the cancer,” Dr. Estabrook said. “Now he’s saying we don’t really have to do that.”
But both Dr. Estabrook and Dr. Port said they would still have to make judgment calls during surgery and remove lymph nodes that looked or felt suspicious.
The new research grew out of efforts in the 1990s to minimize lymph node surgery in the armpit, called axillary dissection. Surgeons developed a technique called sentinel node biopsy, in which they injected a dye into the breast and then removed just one or a few nodes that the dye reached first, on the theory that if the tumor was spreading, cancer cells would show up in those nodes. If there was no cancer, no more nodes were taken. But if there were cancer cells, the surgeon would cut out more nodes.
Although the technique spared many women, many others with positive nodes still had extensive cutting in the armpit, and suffered from side effects.

“Women really dread the axillary dissection,” Dr. Giuliano said. “They fear lymphedema. There’s numbness, shoulder pain, and some have limitation of motion. There are a fair number of serious complications. Women know it.”
After armpit surgery, 20 percent to 30 percent of women develop lymphedema, Dr. Port said, and radiation may increase the rate to 40 percent to 50 percent. Physical therapy can help, but there is no cure.
The complications — and the fact that there was no proof that removing the nodes prolonged survival — inspired Dr. Giuliano to compare women with and without axillary dissection. Some doctors objected. They were so sure cancerous nodes had to come out that they said the study was unethical and would endanger women.
“Some prominent institutions wouldn’t even take part in it,” Dr. Giuliano said, though he declined to name them. “They’re very supportive now. We don’t want to hurt their feelings. They’ve seen the light.”

Chemokines (chemo-attractant cytokines) are a group of small proteins that act together with their cell surface receptors, in development, normal physiology and immune responses, to direct cells to specific locations throughout the body. Cancer cells acquire the ability to subvert the chemokine system, such that these molecules and their receptors become important regulators of cell movement into and out of the tumour microenvironment and major players in cancer biology.

Chemokines and their receptors are involved in all stages of cancer development, influencing the cellular composition of the tumour microenvironment, malignant cell survival and metastatic spread. From their earliest stages, cancers harness this intricate and tightly regulated network to generate a corrupt version of a system that, in healthy vertebrates, is necessary for embryonic development, tissue homeostasis and successful immune responses. A greater understanding of the chemokine system in malignancy can not only give us important new insights into cancer biology but also suggest new treatment approaches. If drugs that target the chemokine system show success in chronic inflammatory disease over the next few years, we have enough preclinical data to warrant trialling them in cancers.

Figure 1. The chemokine wheel. This cartoon shows major constituents of the chemokine systems, the G-protein-coupled cell-surface receptors and the chemokine ligands. The ‘inflammatory’ chemokines are inducible and involved in all aspects of the immune response. The ‘homeostatic’ chemokines are involved in development and normal physiology. Atypical chemokine receptors are generally ‘silent’ and act as negative regulators of the systems, ‘decoys’ that reduce chemokine levels. Viral chemokines and receptors allow the pathogens to modulate immune responses to infection. Inflammatory, homeostatic and atypical chemokine receptors are all found in the tumour microenvironment. Another chemokine receptor, CXCR7, which also binds to CXCL12 and CXCL11, is shown in the homeostatic group, but there is some evidence that it is an atypical chemokine receptor

Chemokines (chemo-attractant cytokines) are a group of small proteins that act together with their cell surface receptors, in development, normal physiology and immune responses, to direct cells to specific locations throughout the body 1 , 2 . Gradients of extracellular matrix-bound or soluble chemokines control leukocyte migration and positioning within tissues and direct their patterns of recirculation by inducing extra- or intravasation. They may also control movement of other cell types, such as adult stem cells and endothelial cells.
The chemokine system evolved with the vertebrates and there are nearly 50 human genes that encode chemokine ligands, with more than 20 corresponding human chemokine receptor genes, the latter being seven-transmembrane G-protein-coupled receptors, GPCRs. Chemokines are divided into four different groups, CXC, CC, CX3C or C, depending on the position of the conserved cysteine residue, and receptor nomenclature essentially follows that of the chemokines, ie CC chemokines bind to CC chemokine receptors, CXC ligands bind to CXC receptors