Although the dioxin receptor, the aryl hydrocarbon receptor (AhR), is considered a major regulator of xenobiotic-induced carcinogenesis, its role in tumor formation in the absence of xenobiotics is still largely unknown. Trying to address this question, we have produced immortalized cell lines from wild-type (T-FGMAhR؉/؉) and mutant (T-FGM-AhR؊/؊) mouse mammary fibroblasts by stable co-transfection with the simian virus 40 (SV-40) large T antigen and proto-oncogenic c-HRas. Both cell lines had a myofibroblast phenotype and similar proliferation, doubling time, SV-40 and c-H-Ras expression and activity, and cell cycle distribution. AhR؉/؉ and AhR؊/؊ cells were also equally able to support growth factor-and anchorage-independent proliferation. However, the ability of T-FGM-AhR؊/؊ to induce subcutaneous tumors (leimyosarcomas) in NOD/ SCID-immunodeficient mice was close to 4-fold lower than T-FGM-AhR؉/؉. In culture, T-FGM-AhR؊/؊ had diminished migration in collagen-I and decreased lamellipodia formation. VEGFR-1/Flt-1, a VEGF receptor that regulates cell migration and blood vessel formation, was also down-regulated in AhR؊/؊ cells. Signaling through the ERK-FAK-PKB/AKT-Rac-1 pathway, which contributes to cell motility and invasion, was also significantly inhibited in T-FGM-AhR؊/؊. Thus, the lower tumorigenic potential of T-FGM-AhR؊/؊ could result from a compromised adaptability of these cells to the in vivo microenvironment, possibly because of an impaired ability to migrate and to respond to angiogenesis.

Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of β1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.

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The cytopathologic findings in 17 patients with hydatid cyst are reported. All patients but one were referred for evaluation of a tumor mass. In 13 patients the aspirated material was diagnostic of hydatid cyst. In four patients only acellular laminated membranes were present in the aspirate and a presumptive cytopathologic diagnosis of hydatid cyst was made. Subsequent histologic studies confirmed the diagnosis of hydatidosis in all patients. No complications were encountered. Fine-needle biopsy appears a safe diagnostic approach in the evaluation of suspected hydatid disease. The presence of acellular laminated membranes confirm the diagnosis of hydatid cyst.