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The immune system detects aberrant, premalignant cells and eliminates them before the development of cancer. Immune cells, including T cells, have been shown to be critical components in eradicating these aberrant cells, and when absent in the host, incidence of cancer increases. Here, we show that CD91, a receptor expressed on antigen-presenting cells, is required for priming immune responses to nascent, emerging tumors. In the absence of CD91, effector immune responses are subdued, and tumor incidence and progression are amplified. We also show that, consequently, tumors that arise in the absence of CD91 express neo-epitopes with indices that are indicative of greater immunogenicity. Polymorphisms in human CD91 that are expected to affect ligand binding are shown to influence antitumor immune responses in cancer patients. This study presents a molecular mechanism for priming immune responses to nascent, emerging tumors that becomes a predictor of cancer susceptibility and progression.

Toll-like receptors (TLRs) enable metazoans to mount effective innate immune responses to microbial and viral pathogens, as well as to endogenous host-derived ligands. It is understood that genetic background of the host can influence TLR responsiveness, altering susceptibility to pathogen infection, autoimmunity and cancer. Macrophage stimulatory protein (MSP), which activates the receptor tyrosine kinase recepteur d'origine nantais (RON), promotes key macrophage functions such as motility and phagocytic activity. MSP also acts via RON to modulate signaling by TLR4, which recognizes a range of pathogen or endogenous host-derived molecules. Here, we show that RON exerts divergent control over TLR4 activity in macrophages from different mouse genetic backgrounds. RON potently modulated the TLR4 response in macrophages from M2-prone FVB mice, as compared with M1-skewed C57Bl6 mice. Moreover, global expression analysis revealed that RON suppresses the TLR4-dependent type-I interferon gene signature only in FVB macrophages. This leads to attenuated production of the potent inflammatory mediator, tumor necrosis factor-α. Eliminating RON kinase activity markedly decreased carcinogen-mediated tumorigenesis in M2/Th2-biased FVB mice. We propose that host genetic background influences RON function, thereby contributing to the variability in TLR4 responsiveness in rodents and, potentially, in humans. These findings provide novel insight into the complex interplay between genetic context and immune function.

A study on the protective effect of alcoholic extract of the leaves of Ocimum sanctum on 3-methylcholanthrene (MCA), 7,12-dimethylbenzanthracene (DMBA) and aflatoxin B1 (AFB1) induced skin tumorigenesis in a mouse model has been investigated. The study involved pretreatment of mice with the leaf extract prior to either MCA application or tetradecanoyl phorbol acetate (TPA) treatment in a two-stage tumor protocol viz a viz, DMBA/TPA and AFB1/TPA. The results of the present study indicate that the pretreatment with alcoholic extract of the leaves of O. sanctum decreased the number of tumors in MCA, DMBA/TPA and AFB1/TPA treated mice. The skin tumor induced animals pretreated with alcoholic extract led to a decrease in the expression of cutaneous gamma-glutamyl transpeptidase (GGT) and glutathione-S-transferase-P (GST-P) protein. The histopathological examination of skin tumors treated with leaf extract showed increased infiltration of polymorphonuclear, mononuclear and lymphocytic cells, decreased ornithine decarboxylase activity with concomitant enhancement of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in the serum, implying the in vivo antiproliferative and immunomodulatory activity of leaf extract. The decrease in cutaneous phase I enzymes and elevation of phase II enzymes in response to topical application of leaf extract prior to MCA, AFB1, DMBA/TPA and AFB1/TPA treatment indicate the possibility of impairment in reactive metabolite(s) formation and thereby reducing skin carcinogenicity. Furthermore, pretreatment of leaf extract in the carcinogen induced animals resulted in elevation of glutathione levels and decrease in lipid peroxidation along with heat shock protein expression, indicating a scavenging or antioxidant potential of the extract during chemical carcinogenesis. Thus it can be concluded that leaf extract of O. sanctum provides protection against chemical carcinogenesis in one or more of the following mechanisms: (i) by acting as an antioxidant; (ii) by modulating phase I and II enzymes; (iii) by exhibiting antiproliferative activity.

Skin tumours were induced in male inbred rats of the Lister and Wistar strains and in (WixBN) F1 hybrids by topical application of 3-methylcholanthrene (MCA) and 7,12-dimethylbenz(alpha)anthracene (DMBA). Several schedules of application were compared. At a weight basis DMBA was more potent than MCA and the tumour response to DMBA was most clearly related to total dose applied, while the frequency of application was very important for the tumour crop on MCA-treated rats. DMBA led to a marked predominance of squamous celled tumours (SQCT) when treatment was potent, while basal celled and adnexal tumours (BCAT) prevailed after any dosage of MCA. The carcinogenic effect of DMBA in a low total dose approached that of the most potent dosage of MCA. At this level of activity DMBA induced more BCAT than SQCT in both strains and in the hybrids, while MCA induced an increased number of SQCT. Strain differences did not interfere with these main results.

The cis-2a,3-diol and the trans-4,5-, trans-7,8-, trans-9,10- and trans-11,12-dihydrodiols of 3-methylcholanthrene and the trans-3,4, trans-5,6-, trans-8,9. and trans-10,11- dihydrodiols of 7,12-dimethylbenz[a]anthrancene have been tested, in comparison with the parent hydrocarbons, for their abilities to initiate skin tumours in female CDI mice. Groups of mice received a single topical application (25 micrograms) of a diol or of a hydrocarbon, and 1 week later repeated topical applications (1 microgram) of 12-0-tetradecanoylphorbol-13-acetate were commenced. The results show that the diol of 3-methylcholanthrene and the 3,4-diol of 7,12-dimethylbenz[a]anthrancene were active as initiating agents but that they were no more active than their parent hydrocarbon. The K-region 5,6-diol of 7,12-dimethylbenz[a]anthrancene, which cannot be converted directly into a vicinal diol-epoxide, was also active as a tumour-initiating agent when applied to mouse skin.