Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain-and loss-of-function experiments, we identified the matricellular protein CYR61 and AVB5 integrin as proteins cooperating to mediate these effects. The anti-AV integrin monoclonal antibody 17E6 and the small molecular AVB3/ AVB5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and AVB5 integrin as proteins that cooperate to mediate metastasis. They also identify AV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences. [Cancer Res 2008;68(18):7323-31]

Tumor-infiltrating lymphocytes are present in a variety of tumors and play a central role in antitumor immune responses. Nevertheless, most cancers progress probably because tumors are only weakly immunogenic and develop multiple immunosuppressive mechanisms. In the present study, on head and neck squamous cell carcinoma, we found high intraepithelial infiltration of regulatory FOXP3 1 T cells, and relatively high levels of BDCA2 1 and FOXP3 1 cells in stromal (peripheral) regions of the tumors. Tumor-infiltrating (intraepithelial) FOXP3 1 T cells were significantly more frequent in patients with oropharynx and oral cavity squamous cell carcinoma and in patients without lymph node metastasis. Furthermore, arginase-II (ARG2) was expressed by 60%, inducible nitric oxide synthetase by 9%, cyclooxygenase-2 by 43%, and B-cell lymphoma 2 (BCL2) by 26% of tumors. Interestingly, the absence of ARG2 expression, enhanced stromal infiltration of CD11c 1 myeloid dendritic cells, and high numbers of FOXP3 1 T cells were each significantly associated with prolonged overall survival, and the latter two parameters were also confirmed by multivariate analysis. For disease-free survival, multivariate analysis revealed significant negative correlations with BCL2 and ARG2 expression by tumor cells. These findings shed new light on mechanisms of cancer progression, and provide rationales for therapeutic inhibition of immunosuppressive mechanisms in head and neck squamous cell carcinoma.Head and neck cancers are among the most common types of human tumors, with an incidence of approximately 600,000 new cases per year worldwide. 1 They are mostly squamous cell carcinomas and arise from the mucosa of the upper aerodigestive tract, including the oral cavity, oropharynx, hypopharynx and larynx. Despite recent advances in diagnosis and treatment which improved the patients' quality of life, the overall 5-year survival rate has not changed significantly in the last two decades and remains roughly 50-59%. 2 Most patients with disseminated metastatic disease have locoregional recurrence diagnosed initially. 3 New treatment modalities such as multiple daily fractionated radiation or docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy have shown promising results. However, toxicity as well as locoregional failure remains a major problem, despite some survival advantage, 4,5 urging the need for innovative therapies, not only to improve functional outcomes without increasing toxicity but also to impact long-term survival in these patients.The immune system plays an important role in controlling tumor development. Indeed, the discovery of T lymphocytes able to specifically recognize tumor cells provided strong evidence that natural immune responses are generated during tumor progression. Numerous studies have shown that various human tumors are infiltrated by T cells (tumorinfiltrating lymphocytes, TILs) 6 and CD8 þ T cells appear to be important in the anticancer immune response. Their infiltration within cancer nests is a relia...

For a long time, intraductal tumors of the pancreas were neglected because they were misdiagnosed as mucinous cystadenocarcinoma, ordinary ductal adenocarcinoma, or chronic pancreatitis. Only in recent years have they been recognized as clinical and pathological entities. Most common are the intraductal papillary-mucinous neoplasms. Although they show an adenoma-carcinoma sequence, they have proved to have a more favorable prognosis than ductal adenocarcinoma, when resected in a preinvasive state. Recently, it has become clear that they constitute a heterogeneous group with at least four subtypes. Their stratification reveals that the various intraductal papillarymucinous neoplasm subtypes have different biological properties with different prognostic implications.Keywords Intraductal papillary mucinous neoplasm . Pancreas . Outcome Historical notes and a rising incidenceThe pancreatic tumors that are characterized by an intraductal origin and growth pattern include intraductal papillarymucinous neoplasms [3,24,41], intraductal tubular carcinomas [22,45], intraductal tubular adenomas of the pyloric type [6], and intraductal acinar cell carcinomas [15]. Most common are the intraductal papillary-mucinous neoplasms (IPMNs). They are mucin-producing epithelial tumors that usually show a papillary architecture and are associated with dilatation of the ducts. Before 1990, these tumors were thought to be rare. They first started to be recognized approximately 20 years ago [31,36,39], when the many different names given to the tumor in the 1980s were replaced by the term IPMN [41]. This name was also introduced in the classification of exocrine pancreatic tumors propagated by the World Health Organization (WHO) [24] and the fascicles of the Armed Forces Institute of Pathology [44]. Since then, IPMNs have been reported with increasing frequency (Table 1) and currently account for about 7% of clinically diagnosed pancreatic neoplasms and up to 16% of surgically resected pancreatic neoplasms and for almost 50% of pancreatic cysts found incidentally [8,17]. When only the cystic tumors of the pancreas are considered, IPMNs take first place, with a frequency of 24% [26].The new incidence data on IPMNs raise the question whether their increase in number is real or not. Of course, it is difficult to accept that IPMNs might have been overlooked in the past, not only clinically but also morphologically. There are good reasons, however, to believe that IPMNs did always exist and did not really increase in frequency. One reason is related to the rapid improvements in modern imaging techniques, which enable more precise recognition of cystic lesions, even if they are small and

PURPOSE: Local breast cancer relapse after breast-saving surgery and radiotherapy is associated with increased risk of distant metastasis formation. The mechanisms involved remain largely elusive. We used the well-characterized 4T1 syngeneic, orthotopic breast cancer model to identify novel mechanisms of postradiation metastasis. EXPERIMENTAL DESIGN: 4T1 cells were injected in 20 Gy preirradiated mammary tissue to mimic postradiation relapses, or in nonirradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histologic analyses, adoptive cell transfer, genetic, and pharmacologic interventions were carried out. RESULTS: Tumors growing in preirradiated mammary tissue had reduced angiogenesis and were more hypoxic, invasive, and metastatic to lung and lymph nodes compared with control tumors. Increased metastasis involved the mobilization of CD11b(+)c-Kit(+)Ly6G(high)Ly6C(low)(Gr1(+)) myeloid cells through the HIF1-dependent expression of Kit ligand (KitL) by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and premetastatic lungs, to give rise to CD11b(+)c-Kit(-) cells. Pharmacologic inhibition of HIF1, silencing of KitL expression in tumor cells, and inhibition of c-Kit with an anti-c-Kit-blocking antibody or with a tyrosine kinase inhibitor prevented the mobilization of CD11b(+)c-Kit(+) cells and attenuated metastasis. C-Kit inhibition was also effective in reducing mobilization of CD11b(+)c-Kit(+) cells and inhibiting lung metastasis after irradiation of established tumors. CONCLUSIONS: Our work defines KitL/c-Kit as a previously unidentified axis critically involved in promoting metastasis of 4T1 tumors growing in preirradiated mammary tissue. Pharmacologic inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy. Clin Cancer Res; 18 (16)