Epithelial cancers are believed to originate from transformation of tissue stem cells. However, bone marrow-derived cells (BMDCs), which are frequently recruited to sites of tissue injury and inflammation, might also represent a potential source of malignancy. We show that although acute injury, acute inflammation, or transient parietal cell loss within the stomach do not lead to BMDC recruitment, chronic infection of C57BL/6 mice with Helicobacter, a known carcinogen, induces repopulation of the stomach with BMDCs. Subsequently, these cells progress through metaplasia and dysplasia to intraepithelial cancer. These findings suggest that epithelial cancers can originate from marrow-derived sources and thus have broad implications for the multistep model of cancer progression.
The tumor microenvironment, composed of non-cancer cells and their stroma, has become recognized as a major factor influencing the growth of cancer. The microenvironment has been implicated in the regulation of cell growth, determining metastatic potential and possibly determining location of metastatic disease, and impacting the outcome of therapy. While the stromal cells are not malignant per se, their role in supporting cancer growth is so vital to the survival of the tumor that they have become an attractive target for chemotherapeutic agents. In this review, we will discuss the various cellular and molecular components of the stromal environment, their effects on cancer cell dynamics, and the rationale and implications of targeting this environment for control of cancer. Additionally, we will emphasize the role of the bone marrow-derived cell in providing cells for the stroma.
Aging is the single most common risk factor for cancer. Peripheral and marrow-derived stem cells are long lived and are candidate cells for the cancer-initiating cell. Repeated rounds of replication are likely required for accumulation of the necessary genetic mutations. Based on the facts that mesenchymal stem cells (MSC) transform with higher frequency than other cell types, and tumors in aged C57BL/6 mice are frequently fibrosarcomas, we used a genetically tagged bone marrow (BM) transplant model to show that aged mice develop MSC-derived fibrosarcomas. We further show that, with aging, MSCs spontaneously transform in culture and, when placed into our mouse model, recapitulated the naturally occurring fibrosarcomas of the aged mice with gene expression changes and p53 mutation similar to the in vivo model. Spontaneously transformed MSCs contribute directly to the tumor, tumor vasculature, and tumor adipose tissue, recruit additional host BM-derived cells (BMDC) to the area, and fuse with the host BMDC. Unfused transformed MSCs act as the cancer stem cell and are able to form tumors in successive mice, whereas fusion restores a nonmalignant phenotype. These data suggest that MSCs may play a key role in age-related tumors, and fusion with host cells restores a nonmalignant phenotype, thereby providing a mechanism for regulating tumor cell activity. [Cancer Res 2007;67(22):10889-98]
Cancer commonly arises at the sites of chronic inflammation and infection. Although this association has long been recognized, the reason has remained unclear. Within the gastrointestinal tract, there are many examples of inflammatory conditions associated with cancer, and these include reflux disease and Barrettos adenocarcinoma of the esophagus, Helicobacter infection and gastric cancer, inflammatory bowel disease and colorectal cancer and viral hepatitis leading to hepatocellular carcinoma. There are several mechanisms by which chronic inflammation has been postulated to lead to cancer which includes enhanced proliferation in an endless attempt to heal damage, the presence of a persistent inflammatory environment creating a pro-carcinogenic environment and more recently a role for engraftment of circulating marrow-derived stem cells which may contribute to the stromal components of the tumor as well as the tumor mass itself. Here we review the recent advances in our understanding of the contributions of circulating bone marrow-derived stem cells to the formation of tumors in animal models as well as in human beings.
The aim of this study was to explore the association of specific microRNAs (miRNAs) with the development of esophageal cancer (EC) and to identify new molecular markers for EC by analyzing the expression profiles of miRNAs in EC tissues. The expression profiles of miRNAs in paired EC and paracancerous normal tissues were detected and bioinformatically analyzed using miRNA assays. The outcomes were validated using real-time polymerase chain reaction. The miRNA assays revealed a total of 60 differentially expressed miRNAs in the EC tissues compared with those in the paracancerous normal tissues. Among them, 51 had doubled or more than doubled their expression levels and 9 had halved their expression levels. The most markedly upregulated miRNAs were hsa-miR-15a, hsa-miR-28-3p, hsa-miR-31, hsa-miR-99b, hsa-miR-101, hsa-miR-130a, hsa-miR-143, hsa-miR-196b, hsa-miR-200a, hsa-miR-210, hsa-miR-452 and hsa-miR-27a, whereas the most markedly downregulated miRNAs included hsa-miR-30b, hsa-miR-223, hsa-miR-454, hsa-miR-486, hsa-miR-574-3p and hsa-miR-126. Specific miRNA expression profiles exist in EC tissues and may serve as novel EC molecular markers.
The host immune response plays a critical role in determining disease manifestations of chronic infections. Inadequate immune response may fail to control infection, although in other cases the specific immune response may be the cause of tissue damage and disease. The majority of patients with chronic infections are infected by more than one organism yet the interaction between multiple active infections is not known, nor is the impact on disease outcome clear. Using the BALB/c strain of mice, we show that Toxoplasma gondii infection in a host infected with Helicobacter felis alters the natural outcome of T. gondii infection, allowing uncontrolled tachyzoite replication and severe organ damage. Survival rates decrease from 95% in T. gondii infection alone to 50% in dual-infected mice. In addition, infection with T. gondii alters the specific H. felis immune response, converting a previously resistant host to a susceptible phenotype. Gastric mucosal IFN-γ and IL-12 were significantly elevated and IL-10 substantially reduced in dual-infected mice. These changes were associated with severe gastric mucosal inflammation, parietal cell loss, atrophy, and metaplastic cell changes. These data demonstrate the profound interactions between the immune response to unrelated organisms, and suggest these types of interactions my impact clinical disease.
Patients at the same pathological stage of esophageal cancer (EC) that received the same surgical therapy by the same surgeon may have distinct prognoses. The current study aimed to explore the possibility of differentiallyexpressed microRNAs (miRNAs) underlying this phenomenon. Samples were collected from EC patients at the same tumor node metastasis (TNM) stage but with different prognoses. Paracancerous normal tissues were taken as controls. The specimens were histopathologically analyzed. Differentially-expressed miRNAs were analyzed using real-time quantitative reverse transcription polymerase chain reaction. Compared with patients with poor prognosis, those with good prognosis exhibited 88 two-fold or more than two-fold increased miRNA fragments and 4 half-decreased miRNAs. The most noticeably up-regulated miRNAs included hsa-miR-31, hsa-miR196b, hsa-miR-652, hsa-miR-125a-5p, hsa-miR-146b, hsa-miR-200c, hsa-miR-23b, hsa-miR-29a, hsa-miR-186, hsa-miR-205, hsa-miR-376a, hsa-miR-410, hsa-miR-532-3p, and hsa-miR-598, whereas the most significantlydownregulated miRNAs were hsa-let-7e, hsa-miR-130b, and hsa-miR-103. EC patients at same TNM stage but with different prognoses show differentially-expressed miRNAs.
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