The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.

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Tumour stem cells and drug resistance

The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism

Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44+CD24+ESA+ phenotype (0.2–0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44+CD24+ESA+ cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44+CD24+ESA+ pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44+CD24+ESA+ pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation. [Cancer Res 2007;67(3):1030–7]

https://cancerres.aacrjournals.org/content/canres/67/3/1030.full.pdf

Identification of Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.

/pdf/inhibition-of-hedgehog-signaling-enhances-delivery-of-4af92tah7e.pdf

Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

Hedgehog signalling--an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer--may also be an important mediator in human pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses.

Pathology and genetics of tumors of the digestive system

In patients with inflammatory bowel disease (IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes.

Vijay Yajnik

Papers

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses.

Pathology and genetics of tumors of the digestive system

Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment.

DOCK4, a GTPase activator, is disrupted during tumorigenesis.