Intratumoral α-SMA Enhances the Prognostic Potency of CD34 Associated with Maintenance of Microvessel Integrity in Hepatocellular Carcinoma and Pancreatic Cancer

Abstract

Microvessel density (MVD) as an angiogenesis predictor is inefficient per se in cancer prognosis. We evaluated prognostic values of combining intratumoral alpha-smooth muscle actin (α-SMA)-positive stromal cell density and MVD after curative resection in hypervascular hepatocellular carcinoma (HCC) and hypovascular pancreatic cancer (PC). Tissue microarrays were constructed from tumors of 305 HCC and 57 PC patients who underwent curative resection and analyzed for α-SMA and CD34 expression by immunostaining. Prognostic values of these two proteins and other clinicopathological features were examined. Both low α-SMA density and high MVD-CD34 were associated in HCC with the presence of intrahepatic metastasis and microvascular invasion, and they were related to lymph node involvement and microvascular invasion in PC (p<0.05). Although CD34 alone, but not α-SMA, was an independent prognostic factor for overall survival and recurrence-free survival, the combination of low α-SMA and high CD34 was a predictor of worst prognosis for both types of tumors and had a better power to predict patient death and early recurrence (p<0.01). Furthermore, the results show that distribution of most of the α-SMA-positive cells and vascular endothelial cells overlap, showing major colocalization on vascular walls. Poor microvessel integrity, as indicated by high MVD, together with low perivascular α-SMA-positive cell coverage is associated with early recurrence, unfavorable metastasis, and short survival after tumor resection. This finding highlights the significance of vascular quality in tumor progression, which provides an optimized complement to vascular quantity in prognosis of postoperative patients.

Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

“…These results suggest that at both early and late stages of pancreatic cancer, fibrosis associated with myofibroblasts and type I collagen constitutes a protective response from the host rather than offering an oncogenic supportive role, as speculated (Armstrong et al, 2004; Omary et al, 2007). This conclusion is supported by the clinical correlation between high αSMA and improved survival, a similar trend was previously reported from analyses also performed on resected tumors from treatment naïve patients (Wang et al, 2013). While other studies have also attempted to specifically address the correlation between relative tumor content in αSMA + myofibroblasts and PDAC patient outcome, potential therapeutic intervention prior to tumor resection make interpretations unclear (Erkan et al, 2008; Mani et al, 2008).…”

Stromal biology and therapy in pancreatic cancer: a changing paradigm

“…Unbiased and joint efforts need to be undertaken to resolve the current discrepancies. While past investigations mainly described a poor prognostic role for stroma-rich PDA,110 recent data contradict these findings and propose that high α-SMA content correlates with increased survival in patients with PDA 98 109 111. One might even imagine a scenario where chemotherapy that targets proliferating cells might be deleterious for tumours with a high mitotic rate in fibroblasts.…”

FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis

“…MVD is the best recognized indicator for evaluating angiogenesis in solid tumors [56]. Immunostaining of a vascular endothelial cell marker such as CD34 is used to evaluate MVD [57–60].…”