The hallmarks of cancer are also the hallmarks of wound healing.

The Hanahan and Weinberg "hallmarks of cancer" papers provide a useful structure for considering the various mechanisms driving cancer progression, and the same might be useful for wound healing. In this Review, we highlight how tissue repair and cancer share cellular and molecular processes that are regulated in a wound but misregulated in cancer. From sustained proliferative signaling and the activation of invasion and angiogenesis to the promoting role of inflammation, there are many obvious parallels through which one process can inform the other. For some hallmarks, the parallels are more obscure. We propose some new prospective hallmarks that might apply to both cancer and wound healing and discuss how wounding, as in biopsy and surgery, might positively or negatively influence cancer in the clinic.

Proteolytic and Opportunistic Breaching of the Basement Membrane Zone by Immune Cells during Tumor Initiation.

Cancer-related inflammation impacts significantly on cancer development and progression. From early stages, neutrophils and macrophages are drawn to pre-neoplastic cells in the epidermis, but before directly interacting, they must first breach the underlying extracellular matrix barrier layer that includes the basement membrane. Using several different skin cancer models and a collagen I-GFP transgenic zebrafish line, we have undertaken correlative light and electron microscopy (CLEM) to capture the moments when immune cells traverse the basement membrane. We show evidence both for active proteolytic burrowing and for the opportunistic use of pre-existing weak spots in the matrix layer. We show that these small holes, as well as much larger, cancer cell-generated or wound-triggered gaps in the matrix barrier, provide portals for immune cells to access cancer cells in the epidermis and thus are rate limiting in cancer progression.

EphA receptors regulate prostate cancer cell dissemination through Vav2-RhoA mediated cell-cell repulsion.

Metastatic prostate cancer cells display EphB receptor-mediated attraction when they contact stromal fibroblasts but EphA-driven repulsion when they contact one another. The impact of these 'social' interactions between cells during cancer cell invasion and the signalling mechanisms downstream of Eph receptors are unclear. Here we show that EphA receptors regulate prostate cancer cell dissemination in a 2D dispersal assay and in a 3D cancer cell spheroid assay. We show that EphA receptors signal via the exchange factor Vav2 to activate RhoA and that both Vav2 and RhoA are required for prostate cancer cell-cell repulsion. Furthermore, we find that in EphA2/EphA4, Vav2 or RhoA siRNA-treated cells, contact repulsion can be restored by partial microtubule destabilisation. We propose that EphA-Vav2-RhoA-mediated repulsion between contacting cancer cells at the tumour edge could enhance their local invasion away from the primary tumour.

A role for the Golgi matrix protein giantin in ciliogenesis through control of the localization of dynein-2.

The correct formation of primary cilia is central to the development and function of nearly all cells and tissues. Cilia grow from the mother centriole by extension of a microtubule core, the axoneme, which is then surrounded with a specialized ciliary membrane that is continuous with the plasma membrane. Intraflagellar transport moves particles along the length of the axoneme to direct assembly of the cilium and is also required for proper cilia function. The microtubule motor, cytoplasmic dynein-2 mediates retrograde transport along the axoneme from the tip to the base; dynein-2 is also required for some aspects of cilia formation. In most cells, the Golgi lies adjacent to the centrioles and key components of the cilia machinery localize to this organelle. Golgi-localized proteins have also been implicated in ciliogenesis and in intraflagellar transport. Here, we show that the transmembrane Golgi matrix protein giantin (GOLGB1) is required for ciliogenesis. We show that giantin is not required for the Rab11-Rabin8-Rab8 pathway that has been implicated in the early stages of ciliary membrane formation. Instead we find that suppression of giantin results in mis-localization of WDR34, the intermediate chain of dynein-2. Highly effective depletion of giantin or WDR34 leads to an inability of cells to form primary cilia. Partial depletion of giantin or of WDR34 leads to an increase in cilia length consistent with the concept that giantin acts through dynein-2. Our data implicate giantin in ciliogenesis through control of dynein-2 localization.

A role for Tctex-1 (DYNLT1) in controlling primary cilium length.

The microtubule motor complex cytoplasmic dynein is known to be involved in multiple processes including endomembrane organization and trafficking, mitosis, and microtubule organization. The majority of studies of cytoplasmic dynein have focused on the form of the motor that is built around the dynein-1 heavy chain. A second isoform, dynein heavy chain-2, and its specifically associated light intermediate chain, LIC3 (D2LIC), are known to be involved in the formation and function of primary cilia. We have used RNAi in human epithelial cells to define the cytoplasmic dynein subunits that function with dynein heavy chain 2 in primary cilia. We identify the dynein light chain Tctex-1 as a key modulator of cilia length control; depletion of Tctex-1 results in longer cilia as defined by both acetylated tubulin labeling of the axoneme and Rab8a labeling of the cilia membrane. Suppression of dynein heavy chain-2 causes concomitant loss of Tctex-1 and this correlates with an increase in cilia length. Compared to individual depletions, double siRNA depletion of DHC2 and Tctex-1 causes an even greater increase in cilia length. Our data show that Tctex-1 is a key regulator of cilia length and most likely functions as part of dynein-2.

Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human.

Linkage analysis and haplotype mapping in interspecific mouse crosses (Mus musculus x Mus spretus) identified the gene encoding Aurora2 (Stk6 in mouse and STK15 in human) as a candidate skin tumor susceptibility gene. The Stk6 allele inherited from the susceptible M. musculus parent was overexpressed in normal cells and preferentially amplified in tumor cells from F(1) hybrid mice. We identified a common genetic variant in STK15 (resulting in the amino acid substitution F31I) that is preferentially amplified and associated with the degree of aneuploidy in human colon tumors. The Ile31 variant transforms rat1 cells more potently than the more common Phe31 variant. The E2 ubiquitin-conjugating enzyme UBE2N was a preferential binding partner of the 'weak' STK15 Phe31 variant form in yeast two-hybrid screens and in human cells. This interaction results in colocalization of UBE2N with STK15 at the centrosomes during mitosis. These results are consistent with an important role for the Ile31 variant of STK15 in human cancer susceptibility.