Mechanical Force and Actin Dynamics during Cutaneous Squamous Cell Carcinoma (cSCC) Progression: Opportunities for Novel Treatment Modalities

Abstract

Cutaneous squamous cell carcinoma (cSCC) accounts for 25% of cutaneous malignancies diagnosed in the Caucasian population. Surgical removal in combination with radio-and chemotherapy is an effective treatment; however, prognosis for patients suffering from aggressive cSCC is still relatively poor. Increasing prevalence coupled with high mortality and morbidity in aggressive metastatic forms of cSCC highlights the need for development of novel targeted therapeutics. Metastasis is a complex process requiring dramatic reorganization of the cell cytoskeleton. Recent studies have highlighted the importance of mechanical forces and actin dynamics in cancer cells' intrinsic ability to invade adjacent tissues, intravasate into vasculature, and ultimately metastasize. Tight regulation of the biochemical and mechanical properties of the actin cytoskeleton drives cellular processes involved in cSCC progression including polarity establishment, morphogenesis, and motility. Here we will provide a short introduction to disease pathogenesis, give an overview of the role of key regulatory proteins governing the mechanical forces and actin dynamics critical to cSCC progression, and describe the contribution of actin remodeling and actomyosin signaling to cSCC progression. We will also discuss how targeting protein regulating mechanical force and actin dynamics may have clinical utility in development of novel treatment modalities for patients suffering from aggressive cSCC.Squamous Cell Carcinoma -Hallmark and Treatment Modalities 2 immunosuppression, the second most common cause, leads to the formation of aggressive cSCC in organ transplant patients, patients on immunomodulatory therapies, and those suffering from recessive dystrophic epidermolysis bullosa, a genetic skin blistering disease [3][4][5]. The incidence of cSCC is higher in individuals who are fair-skinned and have a sun-sensitive phenotype; however, the aggressive forms of cSCC are more common in men and the elderly [3]. Despite its prevalence, the relatively low fatality rate of cSCC means that its health and economic burden is often substantially underestimated [3], albeit latest data showing that in addition to significant morbidity cSCC accounts for up to 8000 deaths per year and costs approximately $4.8 billion annually in USA alone [6].cSCC generally presents as a scaly, red or bleeding abnormal lesion on sunexposed areas, and is associated with relatively benign outcomes and a low risk of metastasis. However, cSCC can demonstrate dramatic histopathological heterogeneity, resulting in a wide range of clinical outcomes [7]. Histopathologic subtypes of cSCC are broadly divided into low-grade SCC (Figure 1A) that are well-differentiated but have low metastatic potential (keratoacanthomas, SCC in situ and verrucous carcinoma), or high-grade SCC (Figure 1B) that are poorly differentiated, have high potential of metastasis and recurrence, and are associated with a poor prognosis for patients (desmoplastic cSCC, adenosquamous cSCC and cSCC associated with non-healing...

Synthesis of First Coumarin Fluorescent Dye for Actin Visualization

“…43 SCC-9 cells also have actin filaments and are used to study the various parameters of actin-related diseases. 44 Hence, these cell lines are best to study the dye related to actin binding. 45,46 Takagi et al recently developed an F-actin-binding dye, named HMRef, on the HeLa cell line.…”

Chondroitin Sulfate Proteoglycan 4 as a Marker for Aggressive Squamous Cell Carcinoma

“…Another pathway by which CSPG4 enhances integrin activity is through intracellular signalling involving Cdc42 (a member of the Rho family of GTPases), the activated-Cdc42-associated kinase-1 (Ack1) and p130cas [ 83 ], all of which have been shown to be critical in transmitting mechanical forces and managing actin dynamics governing SCC development and progression [ 100 , 101 ]. Clustering of CSPG4 has been shown to activate Cdc42 to a GTP-conjugated state.…”

Chondroitin Sulfate Proteoglycan 4 as a Marker for Aggressive Squamous Cell Carcinoma

“…Another pathway by which CSPG4 enhances integrin activity is through intracellular signalling involving Cdc42 (a member of the Rho family of GTPases), the activated-Cdc42-associated kinase-1 (Ack1) and p130cas [83], all of which have been shown to be critical in transmitting mechanical forces and managing actin dynamics governing SCC development and progression [101,102]. Clustering of CSPG4 has been shown to activate Cdc42 to a GTP-conjugated state.…”

“…Furthermore, at least one study has shown that CSPG4-mediated activation of integrin enhances resistance to chemotherapy by sustained activation of the AKT pathway via PI3K [81]. The role of CSPG4 in modulating the cytoskeleton makes it an ideal target of modern anticancer research, given the current interest in proteins involved in regulating mechanical forces and actin dynamics [102].…”