Different patterns of fibronectin and tenascin-C splice variants expression in primary and metastatic melanoma lesions

Abstract

We have investigated the staining patterns of primary and metastatic melanoma lesions using F8, L19 and F16. These three clinical-stage antibodies are currently being studied in clinical trials for the pharmacodelivery of cytokines or therapeutic radionuclides to neoplastic sites in patients with cancer. Frozen sections of 24 primary and 29 metastatic melanoma lesions were stained, using immunofluorescence procedures, with biotinylated preparations of the F8, L19 and F16 antibodies, which are specific to the alternatively spliced extra domain A and extra domain B domains of fibronectin and A1 domain of tenascin-C, respectively. Blood vessels were costained using von Willebrand factor-specific antibodies. In primary cutaneous melanoma lesions, F16 and F8 (but not L19) strongly stained the basal lamina at the interface between epidermis and dermis, with a strikingly complementary pattern. By contrast, metastatic melanoma lesions displayed a strong and diffuse pattern of immunoreactivity with all three antibodies. It was found that the extracellular matrix in melanoma undergoes extensive remodelling during the transition from primary to metastatic lesions. The intense staining of metastatic melanoma lesions by the F8, L19 and F16 antibodies provides a strong rationale for the use of these antibodies and their derivatives for the treatment of melanoma patients and possibly for the personalized choice of the best performing antibody in individual patients.

Splicing factor SRSF6 promotes hyperplasia of sensitized skin

“…In particular, the M2 isoform of Pkm2 is specifically expressed in embryonic tissues and in cancers 40 . Similarly, the long Tnc isoform (+E10-15 or +E10-18 (human)) is expressed in neuronal stem cells and embryonic tissue 41 , and in many types of invasive and metastatic cancer 42-47 . In breast-cancer cells, the two long TNC isoforms, +E10-15 and ΔE14, drive increased cell migration and proliferation in vitro 46 .…”

The antibody-based targeted delivery of TNF in combination with doxorubicin eradicates sarcomas in mice and confers protective immunity

“…Moreover, it remains unclear whether it is better to use the F8 (specific to the EDA domain of fibronectin) or L19 (specific to EDB) for tumour-targeting applications (Schliemann et al , 2009; Berndt et al , 2010; Frey et al , 2011; Schwager et al , 2011). To address these issues in a preclinical model, we performed a comparative immunohistochemical analysis of the two antibodies on sarcoma specimens.…”

Tumor angiogenesis revisited: Regulators and clinical implications

“…Well‐known examples are represented by the alternatively spliced extradomains A and B of fibronectin, as well as the extradomain A1 of tenascin‐C. These splice variants are undetectable in normal adult tissues but become strongly expressed at sites of physiological and tumor angiogenesis . Another marker of angiogenesis, the lipid raft associated protein bone marrow stromal antigen‐2 (Bst‐2) appears to be more restricted to hematological malignancies like lymphomas .…”

“…These splice variants are undetectable in normal adult tissues but become strongly expressed at sites of physiological and tumor angiogenesis. 423,424 Another marker of angiogenesis, the lipid raft associated protein bone marrow stromal antigen-2 (Bst-2) appears to be more restricted to hematological malignancies like lymphomas. 425 To date, antibody-drug conjugates (ADC) and immunocytokines are advancing in clinical trials, 426 the latter with promising results, warranting efforts to precisely characterize their mechanisms of action.…”