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.

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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

Short bowel syndrome (SBS) refers to a malabsorptive state resulting from loss of intestinal structure and/or function due to congenitally absent, extensively resected, and/or diseased bowel. SBS is typically defined by the presence of <200 cm of functional small intestine. Clinical implications of SBS are influenced by the extent and location of resected bowel, viable length and absorptive capacity of remnant bowel, and small intestinal continuity with the colon. Primary management objectives include establishing adequate fluid and electrolyte balance, promoting intestinal adaptation, and providing adequate hydration and nutritional (macro- and micronutrient) support. Pharmacotherapy is generally required in SBS and tailored to mitigate clinical symptoms. Unique facets of medication management in SBS include prescribing higher drug doses and/or alternate drug delivery routes to achieve adequate clinical response in the face of malabsorption. Medication efficacy is further influenced by available absorptive surface area, remnant anatomy, intestinal transit and mucosal contact time, and acid/alkaline environment, among others. The etiology of diarrhea in SBS may be complex and multifactorial; targeted therapeutic strategies addressing rapid intestinal transit, gastric acid hypersecretion, fat malabsorption, and small intestinal bacterial overgrowth must be considered. Two pharmacologic options available for short-term SBS treatment in patients receiving parenteral nutrition and/or intravenous support are: Somatropin (a recombinant form of human growth hormone) and Teduglutide (a glucagon-like peptide-2 analog). These intestinotrophic hormones are progressive pharmacologic extensions of tailored fluid, nutritional, and standard medication management strategies in SBS. Overall, a comprehensive and multidisciplinary treatment approach is paramount, and various regimens may be required. Medication optimization with frequent reassessments over time can moderate clinical consequences and maximize intestinal rehabilitation potential. Surgical management options may be considered in select SBS cases and are briefly discussed.

Vijay Yajnik

Papers

Short Bowel Syndrome: Pharmacotherapy