Serum haptoglobin type and cancer

The distribution of haptoglobin types in 526 cancerous and 430 noncancerous subjects is presented. The frequency of haptoglobin 1 gene, in females, ranged sequentially from 0.264 in patients with cancer of the cervix, uterus, and ovary, through melanoma, breast cancer, cancer of the colon, to 0.467 in reticuloses. This was supported by statistically significant differences observed between some groups of cancer patients and normal controls. A different haptoglobin 1 gene frequency was found for male cancer patients.     

An analogy between the evolution of drug resistance in bacterial communities and malignant tissues

Cancer cells rapidly evolve drug resistance through somatic evolution and, in order to continue growth in the metastatic phase, violate the organism-wide consensus of regulated growth and beneficial communal interactions. We suggest that there is a fundamental mechanistic connection between the rapid evolution of resistance to chemotherapy in cellular communities within malignant tissues and the rapid evolution of antibiotic resistance in bacterial communities. We propose that this evolution is the result of a programmed and collective stress response performed by interacting cells, and that, given this fundamental connection, studying bacterial communities can provide deeper insights into the dynamics of adaptation and the evolution of cells within tumours.     

Serum haptoglobin as a novel molecular biomarker predicting colorectal cancer hepatic metastasis

Early detection of liver metastasis is important for improving colorectal cancer (CRC) patient survival. Our previous studies showed haptoglobin was highly expressed in primary CRC tissues, especially in heterochronous metastatic cases. Here, we assessed the potential of serum haptoglobin (sHP) as a biomarker for early detection of CRC liver metastasis by evaluating the sHP in 475 CRC patients and 152 healthy volunteers. In the training set (250 cases), sHP level in CRC‐M1 (1773.18 ± 690.25 ng/mL) were significantly increased as compared to in CRC‐M0 (1544.37 ± 1497.65 ng/mL) or healthy (917.76 ± 571.59 ng/mL). And the high sHP level was correlated with poor survival. Logistic regression analysis revealed that sHP, serum carcinoembryonic antigen (sCEA) and serum carbohydrate antigen 19.9 (sCA19.9) level were the significant parameters for detecting liver metastasis. In leave‐one‐out‐cross‐validation, these three markers resulted in 89.1% sensitivity and 85.8% specificity for hepatic metastasis detection. In an independent test set (225 cases), receiver operating characteristic curve analysis of sHP in CRC liver metastasis showed an area under the curve of 0.735, with a sensitivity of 87.2% and a specificity of 59.9%. Combination of sHP, sCEA and sCA19.9 improved diagnostic accuracy to 0.880, with a sensitivity of 88.5% and a specificity of 87.8%. Silencing of HP by specific shRNA significantly inhibited the LOVO and SW620 cell invasion, and suppressed xenograft tumor invasive growth. In summary, these results demonstrate that sHP is associated with poor prognosis of CRC patients and that HP promotes colorectal cancer cell invasion. sHP combining with sCA19.9 and sCEA may be used as accurate predictors of CRC liver metastasis.     

Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutic agents in the treatment of pain, inflammation and fever. They may also have a role in the management of cancer prevention, Alzheimer's disease and prophylaxis against cardiovascular disease. These drugs act primarily by inhibiting cyclooxygenase enzyme, which has two isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Selective COX-2 inhibitors provide potent anti-inflammatory and analgesic effects without the side effects of gastric and renal toxicity and inhibition of platelet function. Celecoxib is a potent COX-2 inhibitor being developed for the treatment of rheumatoid arthritis and osteoarthritis. Chemoprevention is the use of pharmacological or natural agents to prevent, suppress, interrupt or reverse the process of carcinogenesis. For this purpose, celecoxib is being used for different cancer types. The effects of NSAIDs on tumor growth remain unclear, but are most likely to be multifocal. In this article, we reviewed COX-2 selectivity, the pharmacological properties of celecoxib, the use of celecoxib for cancer prevention and the mechanisms of chemoprevention.     

An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation

An antagonistic monoclonal antibody, designated EM164, has been developed which binds specifically to the human insulin-like growth factor I receptor (IGF-IR) and inhibits the proliferation and survival functions of the receptor in cancer cells. EM164 was initially selected by a rapid cell-based screen of hybridoma supernatants to identify antibodies that bind to IGF-IR but not to the homologous insulin receptor and that show maximal inhibition of IGF-I-stimulated autophosphorylation of IGF-IR. EM164 binds tightly to IGF-IR with a dissociation constant K(d) of 0.1 nM, inhibits binding of IGF-I and antagonizes its effects on cells completely, and has no agonistic activity on its own. EM164 inhibits IGF-I-, IGF-II-, and serum-stimulated proliferation and survival of diverse human cancer cell lines in vitro, including breast, lung, colon, cervical, ovarian, pancreatic, melanoma, prostate, neuroblastoma, rhabdomyosarcoma, and osteosarcoma cancer lines. It also suppresses the autocrine or paracrine proliferation of several cancer cell lines. EM164 was the most potent antagonistic anti-IGF-IR antibody tested when compared with several commercially available antibodies. The in vitro inhibitory effect could be extended to in vivo tumor models, where EM164 caused regression of established BxPC-3 human pancreatic tumor xenografts in SCID mice. The antitumor effect of treatment with EM164 could be enhanced by combining it with the cytotoxic agent gemcitabine. These data support the development of EM164 as a candidate therapeutic agent that targets IGF-IR function in cancer cells.     

Fucosylated haptoglobin is a novel type of cancer biomarker linked to the prognosis after an operation in colorectal cancer

BACKGROUND:

Fucosylation is a crucial oligosaccharide modification in cancer and inflammation. Total cellular proteins of cancer cells and the sera of patients with cancer both show increased fucosylation levels. Certain kinds of fucosylated proteins can be applied as novel cancer biomarkers in glyco‐proteomic analyses. We previously identified fucosylated haptoglobin (Fuc‐Hpt) as a serologic marker for pancreatic cancer, and recently developed a lectin‐antibody enzyme‐linked immunosorbent assay system for quantifying Fuc‐Hpt. In the present study, we investigated the clinical outcome of Fuc‐Hpt levels in patients with colorectal cancer (CRC), and examined the mechanisms underlying Fut‐Hpt production using a murine tumor transplantation model.

METHODS:

The relationship between Fuc‐Hpt levels and clinical parameters was investigated in 77 patients with CRC, all of whom underwent primary resection. Serum Fuc‐Hpt levels were examined in athymic nude mice injected with colon cancer cell lines that lacked fucosylation.

RESULTS:

Fuc‐Hpt levels were significantly associated with overall and relapse‐free survival, distant metastasis, clinical stage, and curability. Multivariate analysis revealed that distant metastasis was an independent factor for increased Fuc‐Hpt levels. The combination of Fuc‐Hpt and CEA might be a better serologic marker to predict prognosis. Fuc‐Hpt levels were higher in mice with direct injection of tumor cells into the spleen than in those injected subcutaneously.

CONCLUSIONS:

Fuc‐Hpt might be a useful marker for the prognosis of CRC. Fuc‐Hpt could be produced by the tissue surrounding tumor cells, which might be the mechanism underlying Fuc‐Hpt elevation associated with distant metastasis. Cancer 2012;118: 3036–43. © 2011 American Cancer Society.     

Abnormally-fucosylated haptoglobin: a cancer marker for tumour burden but not gross liver metastasis

A previous study has shown that there are high levels of an abnormally-fucosylated form of haptoglobin (FHp) in the blood of cancer patients (Thompson & Turner, 1987b). In this study, we investigated the expression of this substance in serial blood specimens from women with ovarian or breast cancer who were undergoing cytotoxic chemotherapy. The level of FHp was related to patient response to therapy status, this latter index being an indirect determination of tumour burden. FHp levels did not correlate with gross liver metastasis (as shown by CT scans or the blood levels of liver enzymes). This conclusion was further supported by results from patients with hepatocellular cancer. FHp was elevated in most of these patients, but the pattern of change did not correlate with variations in the level of the hepatoma marker, alpha-foetoprotein. It seems likely that FHp is produced by the liver. Primary and secondary tumours could release substances, such as cytokines, which interfere with fucose metabolism in the liver.     

Galectin-3 expression is a potent prognostic marker in colorectal cancer

BACKGROUND: Galectin-3 is a beta-galactoside-binding protein whose expression has been correlated with progression and metastasis in colon cancer. It is expressed at elevated levels in a variety of neoplastic cells. The current study was designed to investigate, by clinicopathological analysis, the relationship between prognosis and galectin-3 expression, in colorectal cancer. PATIENTS AND METHODS: Galectin-3 expression was evaluated using immunohistochemical staining in 121 consecutive patients with colorectal cancer. The relationship between galectin-3 expression and clinicopathological factors was analyzed. RESULTS: Galectin-3-positive expression was detected in 79 patients (65%). The incidence of lymph node and distant metastasis in galectin 3-positive cancer was significantly higher than that in galectin-3-negative cases (p = 0.0007 and p = 0.014, respectively). Furthermore, cancers with galectin-3-positive expression revealed frequent venous invasion (p = 0.005) and lymphatic permeation (p = 0.041), larger size (p = 0.016) and deeper invasion to wall(p = 0.01) than in galectin-3-negative cases. While univariate analysis showed that survival in patients with galectin-3-positive expression was significantly poorer than in galectin-3-negative cases (p = 0.0027), galectin-3 expression was a prognostic factor independent of Dukes' stage and lymph node metastasis by multivariate analysis. CONCLUSION: We propose that galectin-3 expression is an independent factor for prognosis in colorectal cancer.     

Telmisartan is a potent target for prevention and treatment in human prostate cancer

Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agent. Recent studies have reported that ARBs have the potential to inhibit the growth of prostate cancer (PC) cells. Moreover, it was recently reported that Telmisartan (a kind of ARB) has peroxisome proliferator-activated receptor (PPAR)-gamma activation. We previously reported that PPAR-gamma ligand induces growth arrest of PC cells through apoptosis. In this study, we evaluated the effects of the Telmisartan and other ARBs on cell proliferation in several PC cell lines. We used normal prostate stromal cell (NPC), human hormone-refractory PC (PC3), androgen-independent PC (DU-145) and androgen-dependent PC (LNCaP) cell lines. Effects of Telmisartan and other ARBs (Candesartan, Valsartan, Irbesartan and Losartan) on PC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not ARBs induce apoptosis. Telmisartan caused marked inhibition of PC cells in concentration-dependent and time-dependent manner. PC cells with treatment of 100 microM Telmisartan induced early apoptosis and DNA fragmentation. However, NPC with treatment of 100 microM Telmisartan did not induce apoptosis or DNA fragmentation. Furthermore, other ARBs had no effect on cell proliferation in the PC cells and NPC. Telmisartan may mediate potent antiproliferative effects against PC cells through PPAR-gamma. Thus, Telmisartan is a potent target for prevention and treatment in PC.     

Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: identity of a potent new bisphosphonate analogue

While the effects of bisphosphonates on bone-resorbing osteoclasts have been well documented, the effects of bisphosphonates on other cell types are not as well studied. Recently, we reported that bisphosphonates have direct effects on bone-forming human fetal osteoblast cells (hFOB) [1]. In this report, the role of the mevalonate pathway in the actions of bisphosphonates on hFOB, and MDA-MB-231 human breast cancer cells was examined. These studies included a novel bisphosphonate analog, the anhydride formed between arabinocytidine 5 phosphate and etidronate (Ara-CBP). Ara-CBP was the most potent inhibitor of hFOB and MDA-MB-231 cell proliferation, and stimulator of hFOB cell mineralization compared to etidronate, the anhydride formed between AMP and etidronate (ABP), pamidronate, and zoledronate. Inhibition of hFOB cell proliferation by Ara-CBP and zoledronate was partially reversed by mevalonate pathway intermediates, and stimulation of hFOB cell mineralization was completely reversed by mevalonate pathway intermediates. These results suggest that zoledronate and Ara-CBP act, at least in part, via inhibition of the mevalonate pathway in hFOB cells. In contrast, none of the mevalonate pathway intermediates reversed the inhibition of MDA-MB-231 cell proliferation by the bisphosphonates, or the effects of pamidronate on hFOB cells. As a positive control, the effects of mevastatin on hFOB and MDA-MB-231 cells were completely reversed by mevalonate. In summary, these data suggest that zoledronate and Ara-CBP induce human osteoblast differentiation via inhibition of the mevalonate pathway. In contrast, the inhibition of MDA-MB-231 cell proliferation by the bisphosphonates appears to be through mechanisms other than inhibition of the mevalonate pathway.     

Exemestane: a potent irreversible aromatase inactivator and a promising advance in breast cancer treatment

With the introduction of orally-active, potent and selective third-generation aromatase inhibitors and inactivators--anastrozole, letrozole and exemestane--approaches to the treatment of advanced breast cancer are undergoing re-evaluation. In advanced breast cancer, aromatase inhibitors and inactivators are likely to become established as the primary choice over tamoxifen in postmenopausal female breast cancer patients when hormonal therapy is indicated in the first-line setting. The current evaluation of exemestane, an oral steroidal irreversible aromatase inactivator, for primary and adjuvant therapy and the potential role of potent estrogen-deprivation therapy in prevention of postmenopausal breast cancer may extend the use of antiaromatase therapy as an increasingly valuable palliative treatment option, conferring survival benefit and possible preventive outcomes across several treatment settings in the management of breast cancer.     

Exemestane: a potent irreversible aromatase inactivator and a promising advance in breast cancer treatment

With the introduction of orally-active, potent and selective third-generation aromatase inhibitors and inactivators – anastrozole, letrozole and exemestane – approaches to the treatment of advanced breast cancer are undergoing re-evaluation. In advanced breast cancer, aromatase inhibitors and inactivators are likely to become established as the primary choice over tamoxifen in postmenopausal female breast cancer patients when hormonal therapy is indicated in the first-line setting. The current evaluation of exemestane, an oral steroidal irreversible aromatase inactivator, for primary and adjuvant therapy and the potential role of potent estrogen-deprivation therapy in prevention of postmenopausal breast cancer may extend the use of antiaromatase therapy as an increasingly valuable palliative treatment option, conferring survival benefit and possible preventive outcomes across several treatment settings in the management of breast cancer.     

Occurrence of a fetal fibroblast phenotype in familial breast cancer

We have previously shown that fetal and adult human skin fibroblasts display distinctive migratory phenotypes when cultured on 3-dimensional collagen gels in vitro. In the present study, we have used this information to assess the migratory behavior of fibroblasts obtained from patients with either benign or malignant breast disease, and correlated this with the presence of a family history of breast cancer. We have observed that fibroblasts from 17/34 patients with no previous family history of breast cancer displayed fetal-type behavior in our assay system; in contrast, fibroblasts from 15/16 patients with a positive family history of breast cancer behaved abnormally. This apparently increased probability of expressing a fetal-type migratory phenotype in the patients with a family history is statistically significant (p less than 0.008). Skin fibroblasts obtained from 2 healthy and unaffected first-degree relatives (one male and one female) of patients with a family history of breast cancer also exhibited a fetal-type migratory phenotype.     

Novel disubstituted chrysene as a potent agent against colon cancer

Research on polycyclic aromatic hydrocarbons and their derivatives has received significant attention from the scientific community. The present study involved the synthesis of several novel 6,12-disubstituted chrysene derivatives. Nitration of chrysene with nitric acid produced 6,12-dinitrochrysene which when reduced yielded 6,12-diaminochrysene. A coupling reaction of 6,12-diaminochrysene with an acid in the presence of isobutylchloroformate produced amide. The reduction of amide produced an amine. The amino was converted to a hydrochloride salt. The new compounds were characterized through different types of analytical data. One of these compounds demonstrated marked activity in vivo against a colon cancer cell line. Inhibition of the growth of this tumor was best noted at day 20 when each treatment regimen inhibited the average tumor volume by 50%. In a number of in vivo tests in various regimens, the hydrochloride salt demonstrated consistent inhibition of the growth of the cancer HT-29 cell line. Despite the research progress in polycyclic aromatic compounds, the use of these types of molecules as anticancer agents has not been reported systematically.     

An overview of the association between allergy and cancer

Numerous epidemiological studies have evaluated some aspect of the association between a history of allergy and cancer occurrence. In this article, an overview of the epidemiological evidence is presented with a discussion of a number of methodological issues important in this area of study. Literature searches were conducted using the MEDLINE database from 1966 through to August 2005 to identify articles that explored a personal history of allergic disorders as a risk factor for cancer. Although it is difficult to draw conclusions between allergy and cancer at many sites because of insufficient evidence or a lack of consistency both within and among studies completed to date, strong inverse associations have been reported for pancreatic cancer and glioma, whereas lung cancer was positively associated with asthma. Additional studies are needed to confirm these finding and to address the limitations of previous studies, including the validity and reliability of exposure measures and control for confounding. Further, large prospective studies using cancer incidence would be particularly useful, including studies using biological markers of allergic status to reduce potential misclassification and to confirm the results of previous studies based on self-report. There is also a need for further basic research to clarify a potential mechanism, should an association exist.     

KRAS-induced actin-interacting protein: a potent target for obesity, diabetes and cancer

KRAS-induced actin-interacting protein (KRAP) was originally identified as one of the genes deregulated in colorectal cancer. KRAP encodes a cytoplasmic protein associated with filamentous-actin (F-actin), and the amino acid sequences are highly conserved among KRAP orthologues from fish to mammalian species. We demonstrated that KRAP-deficient mice show altered whole-body energy metabolism and resistance to diet-induced obesity and diabetes. Although the precise mechanisms underlying the metabolic phenotypes in the KRAP-deficient mice remain unclear, KRAP is considered to be a target for metabolism-related diseases. Furthermore, several groups have reported that KRAP is a cancer-associated gene. Further studies on the molecular functions of KRAP in physiological tissues could provide a better understanding of various diseases, and opportunities for intervention in various human diseases. In this review, we summarize the current understanding of KRAP and the roles that it plays in a variety of diseases.