Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays

Abstract

The laminin-5 gamma 2 chain (LN-5c2) is known to be a marker of invasion in several cancer types. Our purpose was to examine the prognostic significance of LN-5c2 expression in different areas of individual colorectal cancers (CRCs) by using tissue microarrays (TMAs), and to clarify the optimal areas for prognostic assessment. Using formalin-fixed paraffin-embedded tissue blocks of pT3 primary CRCs resected from 120 patients, we constructed TMA blocks of tissue core specimens taken from the submucosal invasive front, subserosal invasive front, central area, and rolled edge of each tumor. Using these four-point TMA sets, cytoplasmic LN-5c2 expression was immunohistochemically surveyed, and the area-specific prognostic significance of LN-5c2 expression was evaluated. The data revealed that 35, 30, 15 and 10% of the 120 CRCs showed highgrade LN-5c2 expression in the submucosal invasive front, subserosal invasive front, central area and rolled edge, respectively. Disease-specific survival curves for the groups with high-and low-grade LN-5c2 in the submucosal invasive front and subserosal invasive front were different significantly or of marginal difference (respective 5-year survival rates: 54 and 78% for submucosal invasive front (P ¼ 0.030) and 58 and 75% for subserosal invasive front (P ¼ 0.055)). Multivariate analysis revealed that the grades of LN-5c2 expression in submucosal invasive front (hazard ratio ¼ 2.0, P ¼ 0.047) and subserosal invasive front (hazard ratio ¼ 2.9, P ¼ 0.0033) were independent prognostic factors. In contrast, the grades of LN-5c2 expression in the central area and rolled edge did not have a significant impact on patient prognosis. Analysis using area-specific fourpoint TMAs clearly demonstrated that LN-5c2 expression in the invasive front largely influences the degree of clinical aggressiveness of CRC and its tendency to metastasize.

Laminin-332-Integrin Interaction: A Target For Cancer Therapy?

“…It should be noted that, contrary to the above, laminin-332 expression has been reported by a number of groups to be down regulated in colorectal carcinoma, breast cancer, prostate carcinoma, and oral SCC [61,[67][68][69][70][71][72]. There are a number of explanations for this apparent discrepancy.…”

Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

“…This inconsistency between our in vitro data and the pathology of this subset of CRC may be explained by the striking peritumoural lymphocytic infiltration (PTL) seen frequently in sporadic CIMP þ , MSI-H CRC tumors (Jass, 2007). Specifically, an inverse relation is seen between tumor budding and PTL and it has been suggested that the relative lack of tumor budding observed in this CRC subset may well be due to the high PTL frequently seen in CIMP þ , MSI-H CRC tumors (Jass et al, 2003;Shinto et al, 2005). Findings in DNA mismatch repair-proficient CRC suggest that PTL and their associated tumor infiltrating lymphocytes may destroy budding tumor cells (Jass, 2007;Zlobec et al, 2007).…”

Involvement of cyclin D3 in liver metastasis of colorectal cancer, revealed by genome-wide copy-number analysis

“…Recently, expression of laminin-5 gamma 2 chain in the invasive fronts of tumors was found to be an indicator of lymph-node metastasis and patient prognosis, but expression of that gene in the rolled edge was not. 16 It appears that molecules that are important for tumor-cell proliferation and hematogenous recurrence, for example, cyclin D3, and those that are important for stromal invasion and lymph node metastasis, for example, laminin-5 gamma 2 chain, are expressed in different areas to allow the tumor to grow and spread with integrity.…”

“…15 Using tissue blocks prepared from pT3 primary CRCs resected from 120 patients, we constructed tissue-microarray (TMA) blocks of tissue-core specimens taken from the submucosal invasive front, subserosal invasive front, central area, and rolled edge of each tumor. 16 To construct TMA blocks, four tissue cores were taken from each representative tissue block, and these cores were transferred to a recipient block using a Tissue Microarrayer (Beecher Instruments, Silver Spring, MD, USA). We used cores 2.0 mm in diameter and arranged them 0.7-0.8 mm apart in a recipient block, to construct a total of 15 TMA sets comprising 480 core specimens.…”