Stromal responses to carcinomas of the pancreas: Juxtatumoral gene expression conforms to the infiltrating pattern and not the biologic subtype

Abstract

If there is a "science" of tumor-stromal interactions, there must be a set of biologic rules that are organ-site dependent. One way to explore this hypothesis would be to compare the patterns of gene expression of two biologically distinct neoplasms that arise within the same organ site. Using nonradioactive in situ hybridization, we evaluated the gene expression patterns of three genes previously shown to be robust markers of the juxtatumoral stroma within eight infiltrating ductal adenocarcinoma of the pancreas (ApoC1, ApoD and MMP11), and compared these patterns to those associated with seven infiltrating colloid and tubular carcinomas arising in association with intraductal papillary mucinous neoplasms (IPMNs), a histologically distinct form of primary carcinoma of the pancreas, two surgically resected samples of chronic pancreatitis and two surgically resected pancreatic cancer liver metastases. Robust juxtatumoral stromal expression was noted for all three markers within all eight conventional infiltrating ductal adenocarcinoma tissues, but not in samples of chronic pancreatitis. Among the carcinomas arising within an IPMN, expression for all three markers was also noted for five of seven infiltrating carcinomas analyzed. However, when labeling for these three markers was analyzed with respect to infiltrative growth pattern, positive labeling was only seen in areas of tubular (ductal-type) growth and not in areas of colloid carcinoma. This observation was further supported by two infiltrating carcinomas arising in an IPMN that showed both tubular and colloid growth patterns within the same neoplasm indicating the host stromal response observed may relate to infiltrative growth pattern rather than the biology of the primary tumor type. Moreover, these robust patterns within conventional infiltrating ductal adenocarcinomas were not retained within matched metastases to the liver, indicating the importance of the tumor microenvironment in the host stromal response. Juxtatumoral stroma was found to be composed of a least two cell types, tumor-infiltrating macrophages and fibroblasts, highlighting the complexity of tumor-stromal interactions within an infiltrating carcinoma. Since the juxtatumoral gene expression response is the strongest indication of direct communication between stroma and cancer cells, we provide evidence of a stereotypical response to infiltrative growth that might predominate in tumor-stromal interactions independent of cancer type, a finding with clinical implications for therapeutic modalities that target this response in human tumors.

Quantification of nucleic acid quality in postmortem tissues from a cancer research autopsy program

“…Cancer samples showed greater heterogeneity with respect to the most differentially expressed genes. Genes overrepresented in the cancer samples included PSCA [31], MMP3 [32], MMP11 [33] and SOX2 [34]. The small sample size otherwise precluded a more thorough classification of each carcinoma's subtype as recently described [11].…”

Stromal biology of pancreatic cancer

“…Through in situ hybridization on resected human PDAC, several of these invasion-associated genes were found to show patterns of stromal expression with histologic correlates, including genes expressed throughout the stroma and others expressed in the stroma immediately adjacent to the tumor glands, that is, juxtatumoral expression [Ryu et al, 2001;Iacobuzio-Donahue et al, 2002]. Genes showing marked juxtatumoral expression include ApoC1, ApoD, and the matrix metalloproteinase MMP11-gene expression patterns suggesting the presence of discrete interactions between tumor and stroma which may mediate the biological behavior of PDAC [Ricci et al, 2005].…”

“…MMP-7 positivity was significantly correlated with advanced pathologic stages, and patients with MMP-7-positive carcinoma had a shorter survival time than those negative for MMP-7 [Yamamoto et al, 2001]. MMP11 (stromelysin-3) is expressed in PDAC stromal cells in a ''juxta-tumoral'' distribution and may indicate direct communication between tumor and stromal cells [Iacobuzio-Donahue et al, 2002;Ricci et al, 2005].…”

Loss of MTSS1 results in increased metastatic potential in pancreatic cancer

“…Different studies have yielded similar anti-tumorigenic findings where stromal depletion allowed for greater chemotherapy delivery and thus greater tumor cell death [42]. Conversely, the tumor stroma also has been studied in pro-tumorigenic fashion as well where researchers have found evidence of increased communication between the cells of the microenvironment and the tumor epithelium, resulting in its increased oncogenic potential [43, 44]. Needless to say, a better understanding of how the tumor stroma affects all stages of pancreatic tumorigenesis is critical for understanding how to better treat pancreatic cancer.…”