Although the impact of stage migration versus improved regional disease control cannot be separated on basis of the available information, the data provide support in favor of extended lymphadenectomy during potentially curative gastrectomy for gastric cancer.

Even in transmural or serosa-positive gastric cancer with advanced nodal involvement, more extensive LN dissection and analysis influences survival. Stage-based survival prediction depends on total LN number and number of negative LNs. The mechanism remains uncertain, but is not limited to stage migration. ELND during potentially curative gastrectomy is recommended even for advanced gastric cancer.

Stage-based survival prediction of pancreatic cancer is strongly influenced by total LN counts and numbers of negative LNs obtained. Although the mechanism remains unclear and could reflect confounding factors (margin status and institutional volume), an attempt to resect and examine at least 15 LNs to yield preferably between 10 and 15 negative LNs seems sensible for curative-intent pancreatectomy.

Neovascularization is essential for growth and spread of primary and metastatic tumors. We have identified a novel cytokine, endothelial-monocyte activating polypeptide (EMAP) II, that potently inhibits tumor growth, and appears to have antiangiogenic activity. Mice implanted with Matrigel showed an intense local angiogenic response, which EMAP II blocked by 76% (P < 0.001). Neovascularization of the mouse cornea was similarly prevented by EMAP II (P < 0.003). Intraperitoneally administered EMAP II suppressed the growth of primary Lewis lung carcinomas, with a reduction in tumor volume of 65% versus controls (P < 0.003). Tumors from human breast carcinoma–derived MDA-MB 468 cells were suppressed by >80% in EMAP II–treated animals (P < 0.005). In a lung metastasis model, EMAP II blocked outgrowth of Lewis lung carcinoma macrometastases; total surface metastases were diminished by 65%, and of the 35% metastases present, ≈80% were inhibited with maximum diameter <2 mm (P < 0.002 vs. controls). In growing capillary endothelial cultures, EMAP II induced apoptosis in a time- and dose-dependent manner, whereas other cell types were unaffected. These data suggest that EMAP II is a tumor-suppressive mediator with antiangiogenic properties allowing it to target growing endothelium and limit establishment of neovasculature.

Transforming growth factor-␤ (TGF-␤) suppresses tumor formation by blocking cell cycle progression and maintaining tissue homeostasis. In pancreatic carcinomas, this tumor suppressive activity is often lost by inactivation of the TGF-␤-signaling mediator, Smad4. We found that human pancreatic carcinoma cell lines that have undergone deletion of MADH4 constitutively expressed high endogenous levels of phosphorylated receptor-associated Smad proteins (pR-Smad2 and pR-Smad3), whereas Smad4-positive lines did not. These elevated pR-Smad levels could not be attributed to a decreased dephosphorylation rate nor to increased expression of TGF-␤ type I (T␤R-I) or type II (T␤R-II) receptors. Although minimal amounts of free bioactive TGF-␤1 and TGF-␤2 were detected in conditioned medium, treatment with a pan-specific (but not a TGF-␤3 specific) TGF-␤-neutralizing antibody and with anti-␣ V ␤ 6 integrin antibody decreased steady-state pSmad2 levels and activation of a TGF-␤-inducible reporter gene in neighboring cells, respectively. Thus, activation of TGF-␤ at the cell surface was responsible for the increased autocrine endogenous and paracrine signaling. Blocking T␤R-I activity using a selective kinase inhibitor (SD-093) strongly decreased the in vitro motility and invasiveness of the pancreatic carcinoma cells without affecting their growth characteristics, morphology, or the subcellular distribution of E-cadherin and F-actin. Moreover, exogenous TGF-␤ strongly stimulated in vitro invasiveness of BxPC-3 cells, an effect that could also be blocked by SD-093. Thus, the motile and invasive properties of Smad4-deficient pancreatic cancer cells are at least partly driven by activation of endogenous TGF-␤ signaling. Therefore, targeting the T␤R-I kinase represents a potentially powerful novel therapeutic approach for the treatment of this disease.