Presence of CrkI-containing microvesicles in squamous cell carcinomas could have ramifications on tumor biology and cancer therapeutics.

Recently, we described a phenomenon whereby apoptotic cells generate and release CrkI-containing microvesicles, which stimulate proliferation in surrounding cells upon contact to compensate for their own demise. We termed these microvesicles ACPSVs for Apoptotic Compensatory Proliferation Signaling microvesicles. As immune cells and a majority of current cancer therapeutics destroy tumor cells primarily by apoptosis, we conducted a small pilot study to assess the possibility that ACPSVs may also be generated in squamous cell carcinomas. We first evaluated a primary and a metastatic squamous cell carcinoma cancer cell lines for their ability to produce ACPSVs under normal and apoptotic conditions. We next conducted a pilot study to assess the occurrence of ACPSVs in solid tumors extracted from 20 cancer patients with squamous cell carcinomas. Both cancer cell lines produced copious amounts of ACPSVs under apoptotic conditions. Interestingly, the metastatic squamous cell carcinoma cancer cell line also produced high levels of ACPSVs under healthy condition, suggesting that the ability to generate ACPSVs may be hijacked by these cells. Importantly, ACPSVs were also abundant in the solid tumors of all squamous cell carcinoma cancer patients. Detection of ACPSVs in cancer has potentially important ramifications in tumor biology and cancer therapeutics which warrants further investigation

STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy

BACKGROUND: Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1(H) genotype) are selected by the lung microenvironment. STAT1(H) tumor cells also demonstrate resistance to IFN-gamma (IFNgamma), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1(L) genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress. CONCLUSIONS: Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization

Prognosis and risk factors for early-stage adenoid cystic carcinoma of the major salivary glands

BACKGROUND: Adenoid cystic carcinoma (ACC) is characterized by slow growth, frequent local recurrences, and distant metastasis (DM). However, these findings frequently are reported in patients with advanced-stage tumors, but the outcomes of early-stage tumors are poorly defined. We sought to evaluate the risk factors for the development of DM in early-stage ACC. METHODS: We retrospectively reviewed the charts of 60 patients who were diagnosed with clinical early-stage (T1-2/N0) ACC to determine the risk factors for development of DM and survival of these patients. RESULTS: DM was detected in 12 (20%) of the patients, with a median latency of 31.5 months after diagnosis. Univariate analysis revealed that DM was associated with age =45 years, pathologically positive lymph nodes, extracapsular spread (ECS) from lymph nodes, high-grade histology, and solid tumor subtype. Multivariate analysis revealed solid tumor subtype and ECS to be significantly associated with DM. Disease-specific survival rates at 5 and 10 years for patients with DM were 80% and 40%, respectively, and were both 100% for patients without DM. CONCLUSION: Although the majority of patients with clinical early-stage ACC of the major salivary glands have favorable prognosis, a significant percentage of patients will develop DM. Solid tumor subtype and nodal ECS were independent predictors of DM in early-stage ACC of major salivary glands. Other clinical and pathological variables may also contribute. These subgroups had poor overall and disease-specific survival. Such patients should be observed closely for the development of DM. Systemic therapy should be considered at the time of diagnosis. Cancer 2011. (c) 2011 American Cancer Society

STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy

Background: Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress.Methodology/Principal Findings: Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1H genotype) are selected by the lung microenvironment. STAT1H tumor cells also demonstrate resistance to IFN-gamma (IFNγ), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1L genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress.Conclusions: Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization.</p