Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to “awaken,” resume proliferating and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin alpha-3beta-1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.

Even though the retinoblastoma gene is one of the best-studied tumor suppressor genes, little is known about its functional role. Like all tumor suppressor gene products, the retinoblastoma protein (pRB) is thought to inhibit some aspect of cell proliferation. It also appears to be a cellular target of several DNA tumor virus-transforming proteins, such as adenovirus ElA, human papillomavirus E7, or simian virus 40 large T antigen. To help in the analysis of pRB, we have prepared a new set of anti-human pRB monoclonal antibodies. In addition to being useful reagents for the study of human pRB, these antibodies display several unexpected properties. They can be used to distinguish different subsets of the pRBs on the basis of their phosphorylation states. Some are able to recognize pRB homologs in other species, including mice, chickens, and members of the genus Xenopus. In addition, some of these antibodies can bind directly to other cellular proteins that, like pRB, were originally identified through their association with adenovirus ElA. These immunologically cross-reactive proteins include the p107 and p300 proteins, and their recognition by antibodies raised against pRB suggests that several members of the ElA-targeted cellular proteins form a structurally and functionally related family.Studies of the retinoblastoma gene (RBI) have greatly enforced the notion that tumor development is advanced not only by the gain of dominantly acting mutations but also by the loss of proteins that normally restrict cell growth (1,27,37). Inactivation of both alleles of the RBI gene has been found in all retinoblastoma tumors that have been studied to date, as well as in many small-cell lung carcinomas, osteosarcomas, breast carcinomas, soft tissue sarcomas, bladder carcinomas, and prostate carcinomas (3, 5, 7, 11, 13, 18-20, 26, 31-36, 41, 43). Evidence to support the notion that retinoblastoma protein (pRB) acts as a tumor suppressor comes from studies that show that the reintroduction of a wild-type pRB cDNA into cells without a functional retinoblastoma gene suppresses or delays tumorigenesis (4, 22).The RBI gene product (pRB) also forms a complex with several DNA tumor viral oncoproteins, including the adenovirus ElA proteins, the polyomavirus large T antigens, and human papillomavirus E7 proteins (6, 9, 30, 38). More important, genetic studies have shown that the sequences required for these oncoproteins to form complexes with pRB are also needed for oncogenesis (6,10,28,29,39,40). These studies strongly suggest that binding to pRB is essential for the oncogenic properties of these viral proteins. Moreover, the sequences essential for pRB to interact with ElA or simian virus 40 (SV40) T antigen are frequently mutated in the naturally occurring pRB mutants (21,23,24

The TATA box-binding protein (TBP) is a key transcription factor required for transcription by all three eukaryotic RNA polymerases. It consists of a conserved carboxy-terminal DNA binding domain and a highly divergent amino terminal domain. TBP and different sets of TBP-associated factors (TAFs) constitute at least four multisubunit complexes referred to as SL1, TFIID, TFIIIB, and SNAPC. SL1, TFIID, and TFIIIB are required for transcription by RNA polymerases I, II, and III, respectively, while the SNAP complex is involved in transcription of the small nuclear RNA (snRNA) genes by RNA polymerases II and III. TBP also associates with a number of basal transcription factors such as TFIIA and TFIIB, and with several regulatory factors such as VP16, E1A, and p53. Here we describe the characterization of a panel of monoclonal antibodies (MAbs) directed against the amino-terminal domain of human TBP. These MAbs recognize different TBP epitopes, some of which have been precisely defined. Different MAbs recognize different TBP-containing complexes and several of them crossreact with TBP from other species. These antibodies can be used to purify TBP-containing complexes in a functional form and should be useful to identify new protein-protein interactions involving TBP.

Even though the retinoblastoma gene is one of the best-studied tumor suppressor genes, little is known about its functional role. Like all tumor suppressor gene products, the retinoblastoma protein (pRB) is thought to inhibit some aspect of cell proliferation. It also appears to be a cellular target of several DNA tumor virus-transforming proteins, such as adenovirus E1A, human papillomavirus E7, or simian virus 40 large T antigen. To help in the analysis of pRB, we have prepared a new set of anti-human pRB monoclonal antibodies. In addition to being useful reagents for the study of human pRB, these antibodies display several unexpected properties. They can be used to distinguish different subsets of the pRBs on the basis of their phosphorylation states. Some are able to recognize pRB homologs in other species, including mice, chickens, and members of the genus Xenopus. In addition, some of these antibodies can bind directly to other cellular proteins that, like pRB, were originally identified through their association with adenovirus E1A. These immunologically cross-reactive proteins include the p107 and p300 proteins, and their recognition by antibodies raised against pRB suggests that several members of the E1A-targeted cellular proteins form a structurally and functionally related family.

Short-term in vitro culture of Babesia microti was obtained. Immune hamster serum had an inhibitory effect on the growth of B. microti in vitro. It is suggested that these antibodies act by preventing penetration of erythrocytes by the parasite.