Loss of the α2β1 Integrin Alters Human Papilloma Virus-Induced Squamous Carcinoma Progression In Vivo and In Vitro

Abstract

Expression of the α2β1 integrin, a receptor for collagens and laminin, is altered during tumor progression. Recent studies have linked polymorphisms in the α2 integrin gene with oral, squamous cell carcinoma (SCC). To determine the α2β1 integrin's role in SCC progression, we crossed α2-null mice with K14-HPV16 transgenic animals. Pathological progression to invasive carcinoma was evaluated in HPV-positive, α2-null (HPV/KO) and HPV-positive, wild-type (HPV/WT) animals. α2β1 integrin expression stimulated progression from hyperplasia and papillomatosis to dysplasia with concomitant dermal mast cell infiltration. Moreover, lymph node metastasis was decreased by 31.3% in HPV/KO, compared to HPV/WT, animals. To evaluate the integrin-specific impact on the malignant epithelium versus the microenvironment, we developed primary tumor cell lines. Although transition from dysplasia to carcinoma was unaltered during spontaneous tumor development, isolated primary HPV/KO SCC cell lines demonstrated decreased migration and invasion, compared to HPV/WT cells. When HPV/WT and HPV/KO SCC cells were orthotopically injected into WT or KO hosts, tumor α2β1 integrin expression resulted in decreased tumor latency, regardless of host integrin status. HPV/WT SCC lines failed to demonstrate a proliferative advantage in vitro, however, the HPV/WT tumors demonstrated increased growth compared to HPV/KO SCC lines in vivo. Although contributions of the integrin to the microenvironment cannot be excluded, our studies indicate that α2β1 integrin expression by HPV-transformed keratinocytes modulates SCC growth and progression.

The integrin–collagen connection – a glue for tissue repair?

“…At other stages, however, high expression on metastasizing cells could direct these cells to collagen-rich tissues, such as bone (Hall et al, 2006). α2β1 is known to affect tumor growth and metastasis in a mouse model of squamous carcinoma (Tran et al, 2011), and high α2β1 expression has been reported to accelerate experimental metastasis in melanoma and gastric and colon cancer (Baronas-Lowell et al, 2004;Bartolomé et al, 2014;Matsuoka et al, 2000). Clinical trials are in progress for treating metastatic colon cancer by using a smallmolecule inhibitor of α2β1, the sulphonamide E7820, (Mita et al, 2011).…”

Focal adhesion complex proteins in epidermis and squamous cell carcinoma

“…[41][42][43][44] However, integrin α2 was shown to play a key role in HPV-driven SCC tumorigenesis and metastasis. 45 K14-HPV16/ITGA2 −/− mice had reduced lymph node metastases in comparison to K14-HPV16/ ITGA2 +/+ mice. 45 In addition, SCC cell lines developed from tumors in the K14-HPV16/ITGA2 −/− mice had reduced tumor growth and increased tumor latency compared with SCC lines derived from K14-HPV16/ITGA2 +/+ mice.…”

“…45 In addition, SCC cell lines developed from tumors in the K14-HPV16/ITGA2 −/− mice had reduced tumor growth and increased tumor latency compared with SCC lines derived from K14-HPV16/ITGA2 +/+ mice. 45 While it remains to be seen whether this metastasis phenotype is microenvironmentdependent, this study indicates that targeting integrin α2 may be a viable therapeutic target for HPV-driven SCC.…”

A 3D matrix platform for the rapid generation of therapeutic anti-human carcinoma monoclonal antibodies

“…Indeed, in contrast to these findings, targeting α 2 β 1 with either functionblocking antibodies or shRNA-based strategies has been reported to block metastatic activity in a number of animal model systems (50)(51)(52)(53). Likewise, in a second in vivo model of cancer progression using α 2 -null mice bred into a K14-HPV16 transgenic line, squamous carcinoma cell proliferation and metastatic activities were decreased in the absence of the α 2 integrin (54).…”