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Mouse models of breast cancer have revealed that tumour‐bearing hosts must express the oxidoreductase CLIC4 to develop lung metastases. In the absence of host CLIC4, primary tumours grow but the lung premetastatic niche is defective for metastatic seeding. Primary breast cancer cells release EVs that incorporate CLIC4 as cargo and circulate in plasma of wildtype tumour‐bearing hosts. CLIC4‐deficient breast cancer cells also form tumours in wildtype hosts and release EVs in plasma, but these EVs lack CLIC4, suggesting that the tumour is the source of the plasma‐derived EVs that carry CLIC4 as cargo. Paradoxically, circulating EVs are also devoid of CLIC4 when CLIC4‐expressing primary tumours are grown in CLIC4 knockout hosts. Thus, the incorporation of CLIC4 (and perhaps other factors) as EV cargo released from tumours involve specific signals from the surrounding stroma determined by its genetic composition. Since CLIC4 is also detected in circulating EVs from human breast cancer patients, future studies will address its association with disease. [ABSTRACT FROM AUTHOR]

Transforming growth factor β1 (TGFβ1) expression is elevated by tumor promoters in the mouse skin, but its role in tumor promotion has not been well defined. To investigate this, we have compared TGFβ1+/+ and +/− mice in a two-stage skin chemical carcinogenesis protocol. Surprisingly, TGFβ1+/− mice had fewer number and incidence of benign papillomas, reduced epidermal and tumor cell proliferation and reduced epidermal TGFβ1 and nuclear p-Smad2 localization in response to the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) compared with TGFβ1+/+ mice. Maximal TPA activation of protein kinase C (PKCα) as measured by activity assays and activation of target genes and induction of cornified envelopes correlated with TGFβ1 gene dosage in keratinocytes and addition of exogenous TGFβ1 restored the cornification defect in TGFβ1+/− keratinocytes. Similarly, inhibition of ALK5-suppressed TPA-mediated PKCα activation suggesting that physiological levels of TGFβ1 are required for maximal activation of PKC-dependent mitogenic responses. Paradoxically, the TPA-induced inflammatory response was greater in TGFβ1+/− skin, but TGFβ1+/+ papillomas had more tumor infiltrating myeloperoxidase-positive cells and pro-inflammatory gene expression was elevated in v-rasHa-transduced TGFβ1+/+ but not TGFβ1+/− keratinocytes. Thus, ras activation switches TGFβ1 to a pro-inflammatory cytokine. Despite this differential proliferative and inflammatory response to TPA and enhanced papilloma formation in the TGFβ1+/+ mice, the frequency of malignant conversion was reduced compared with TGFβ1+/− mice. Therefore, TGFβ1 promotes benign tumors by modifying tumor promoter-induced cell proliferation and inflammation but retains a suppressive function for malignant conversion. [ABSTRACT FROM PUBLISHER]

Abstract: Neoplastic cells at various stages of tumor progression may remain dormant for many years. The suppression of the neoplastic phenotype and tumor outgrowth depends on close contact of neoplastic cells with surrounding normal cells. This review examines the nature of these contacts primarily in models for skin cancer induction. Junctional complexes, membrane associated growth factors and their receptors, and paracrine mechanisms likely contribute to this state of tumor cell dormancy. Understanding these mechanisms will be important in primary cancer prevention and for counteracting recurrences in cancer survivors. [Copyright &y& Elsevier]

Studies performed on mouse skin have indicated that chemical carcinogenesis can be subdivided into two distinct stages, initiation and promotion. Initiation results from exposure to a classical mutagenic carcinogen and is irreversible even after a single exposure. The permanently altered initiated cell and its progeny may never form a tumor or in any way be recognizable in the target tissue, Exposure to tumor promoters permits the expression of the neoplastic change in initiated cells, and tumors develop. In contrast to initiators, promoters must be given repeatedly to be effective; individual exposures are reversible, A similar biology is suggested by epidemiologic studies of certain human cancers, particularly lung, breast, colon, and uterine malignancies. Studies in mouse skin cell culture have provided new insights into the changes associated with initiation and promotion. Initiated cells appear to be resistant to signals for terminal differentiation and can proliferate under conditions where normal epidermal cells are obligated to cease proliferation and begin their maturation program. This change is essential for an epithelial tumor cell since it provides the ability to grow away from a basement- membrane attachment site, In cultured epidermal cells, tumor promoters are capable of selectively stimulating the growth of certain cells, including initiated cells, while simultaneously inducing terminal differentiation in other epidermal cells, The net effect of these responses to promoters is the clonal expansion of cells stimulated to proliferate. In this way, promoters are capable of increasing the clone size of initiated cells. These cell culture data provided a biological framework for under- standing initiation and promotion in terminally differentiating epithelial tissues. [ABSTRACT FROM AUTHOR]

Skin tumors chemically induced in mice have provided an important experimental model for studying carcinogenesis and for bioassaying carcinogenic agents. The information obtained from this model suggests that the events leading to tumor formation can be divided into at least two stages, initiation and promotion. A single small. dose of carcinogen produces initiation which appears to be irreversible. These initiating agents may have to be metabolically activated and can interact with cellular macromolecules. The extent to which they bind to DNA correlates well with their carcinogenicity. Increased DNA replication at the time of or during the first day after these agents have been applied appears to enhance carcinogenesis. Unlike initiation, promotion appears to be reversible and the promoting agents must be applied repeatedly before tumors are formed. Promoters interact with membranes, stimulate and alter genetic expression, and increase the rate of cell proliferation. The knowledge gained from these studies in mouse skin has immeasurably helped the entire field of chemical carcinogenesis. But efforts to determine the cellular and molecular mechanisms involved in the carcinogenic process, particularly in the skin, have been hampered by the difficulties of working on whole animals and by the special problems associated with the biologic and biochemical methods required for this target organ. Such problems, however, can be solved by the use of cell cultures of mouse epidermis which can metabolize and bind carcinogens just as is done in vivo. The fact that epidermal cells in vitro proliferate synchronously should facilitate the study of the relation between the cell cycle and carcinogenesis. These cells repair chemically induced DNA damage by at least two mechanisms, excision repair and base-specific repair. [ABSTRACT FROM AUTHOR]

Chloride intracellular channel (CLIC)4 is a p53- and tumor necrosis factor α (TNFα)-regulated chloride channel protein that is localized to the mitochondria and cytoplasm of mouse and human keratinocytes. CLIC4 protein increases in differentiating keratinocytes and in keratinocytes exposed to DNA-damaging agents and metabolic inhibitors. Increasing CLIC4 levels by transduction of recombinant CLIC4 causes apoptosis. CLIC4 translocates to the nucleus under a variety of conditions of cell stress, and nuclear CLIC4 is associated with cell cycle arrest and accelerated apoptosis. Reduction of CLIC4 and several other CLIC family members by expressing a doxycycline-regulated CLIC4 antisense also causes apoptosis in squamous cancer cell lines. Expressing antisense CLIC4 in tumors derived from transplanting these cells into nude mice inhibits tumor growth, increases tumor apoptosis, and reduces tumor cell proliferation. Co-administration of TNFα intraperitoneally enhances the tumor-inhibitory influence of CLIC4 antisense expression. Together, these results suggest that CLIC4 is important for keratinocyte viability and may be a novel target for anti-cancer therapy. [ABSTRACT FROM AUTHOR]