Integrin alpha2 mediates selective metastasis to the liver.

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin alpha2. The direct role of integrin alpha2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin alpha2-mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV-dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin alpha2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin alpha2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.

Live attenuated Listeria monocytogenes effectively treats hepatic colorectal cancer metastases and is strongly enhanced by depletion of regulatory T cells.

The liver represents a major and frequently sole site of metastases for many types of cancer, particularly gastrointestinal cancers. We showed previously that coadministration of an engineered hepatic-targeting Listeria monocytogenes (LM) with a cancer vaccine enhanced the antitumor effect of vaccine-induced T cells selectively against hepatic metastases. Here, we show that administration of multiple doses of LM, in the absence of vaccine, generates therapeutic responses against hepatic metastases. LM treatment of mice bearing hepatic metastases induced tumor-specific CD8+ T-cell responses that were enhanced by depletion of regulatory T (Treg) cells by either anti-CD25 or cyclophosphamide treatment. Antitumor activity of LM further depended on natural killer (NK) cell activation but was inhibited by presence of a subset of NK T cells. These results show the utility of LM in the treatment of hepatic metastases even in the absence of vaccine administration and further suggest that blockade of Treg cells and NK T cells will enhance antitumor activity.

Selective targeting of antitumor immune responses with engineered live-attenuated Listeria monocytogenes.

Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes.

Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study.

OBJECTIVE: To determine whether patients with moderate to severe acne who were treated with isotretinoin experienced significant increases in depressive symptoms over a 3- to 4-month period compared with patients who received conservative acne therapy. DESIGN: Cohort study. SETTING: Hospital-affiliated and community-based clinics in St Louis, Mo. PARTICIPANTS: One hundred thirty-two subjects aged 12 to 19 years with moderate to severe acne. MAIN OUTCOME MEASURES: Depressive symptoms were assessed using the Center for Epidemiological Studies Depression Scale (CES-D), a standardized self-reported instrument. Mean CES-D scores were compared between treatment groups, as were the prevalence and incidence of scores suggestive of clinically significant depression (CES-D score >16). RESULTS: A total of 101 subjects completed the study. At follow-up, CES-D scores (adjusted for baseline CES-D score and sex of patient) suggestive of clinically significant depression were no more prevalent in the isotretinoin group than in the conservative therapy group. Similarly, the incidence (new onset) of depressive symptoms suggestive of clinical significance also was not significantly different between the treatment groups. CONCLUSIONS: The use of isotretinoin in the treatment of moderate-severe acne in adolescents did not increase symptoms of depression. On the contrary, treatment of acne either with conservative therapy or with isotretinoin was associated with a decrease in depressive symptoms.